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Background Clear recognition of the damaging effects of poverty on early childhood development has fueled an interest in interventions aimed at mitigating these harmful consequences. Psychosocial interventions aimed at alleviating the negative impacts of poverty on children are frequently shown to be of benefit, but effect sizes are typically small to moderate. However, averaging outcomes over an entire sample, as is typically done, could underestimate efficacy because weaker effects on less susceptible individuals would dilute estimation of effects on those more disposed to respond. This study investigates whether a genetic polymorphism of the serotonin transporter gene moderates susceptibility to a psychosocial intervention. Methods and findings We reanalyzed data from a randomized controlled trial of a home-visiting program delivered by community health workers in a black, isiXhosa-speaking population in Khayelitsha, South Africa. The intervention, designed to enhance maternal-infant attachment, began in the third trimester and continued until 6 mo postpartum. Implemented between April 1999 and February 2003, the intervention comprised 16 home visits delivered to 220 mother–infant dyads by specially trained community health workers. A control group of 229 mother–infant dyads did not receive the intervention. Security of maternal-infant attachment was the main outcome measured at infant age 18 mo. Compared to controls, infants in the intervention group were significantly more likely to be securely attached to their primary caregiver (odds ratio [OR] = 1.7, p = 0.029, 95% CI [1.06, 2.76], d = 0.29). After the trial, 162 intervention and 172 control group children were reenrolled in a follow-up study at 13 y of age (December 2012–June 2014). At this time, DNA collected from 279 children (134 intervention and 145 control) was genotyped for a common serotonin transporter polymorphism. There were both genetic data and attachment security data for 220 children (110 intervention and 110 control), of whom 40% (44 intervention and 45 control) carried at least one short allele of the serotonin transporter gene. For these 220 individuals, carrying at least one short allele of the serotonin transporter gene was associated with a 26% higher rate of attachment security relative to controls (OR = 3.86, p = 0.008, 95% CI [1.42, 10.51], d = 0.75), whereas there was a negligible (1%) difference in security between intervention and control group individuals carrying only the long allele (OR = 0.95, p = 0.89, 95% CI [0.45, 2.01], d = 0.03). Expressed in terms of absolute risk, for those with the short allele, the probability of secure attachment being observed in the intervention group was 84% (95% CI [73%, 95%]), compared to 58% (95% CI [43%, 72%]) in the control group. For those with two copies of the long allele, 70% (95% CI [59%, 81%]) were secure in the intervention group, compared to 71% (95% CI [60%, 82%]) of infants in the control group. Controlling for sex, maternal genotype, and indices of socioeconomic adversity (housing, employment, education, electricity, water) did not change these results. A limitation of this study is that we were only able to reenroll 49% of the original sample randomized to the intervention and control conditions. Attribution of the primary outcome to causal effects of intervention in the present subsample should therefore be treated with caution. Conclusions When infant genotype for serotonin transporter polymorphism was taken into account, the effect size of a maternal-infant attachment intervention targeting impoverished pregnant women increased more than 2.5-fold when only short allele carriers were considered (from d = 0.29 for all individuals irrespective of genotype to d = 0.75) and decreased 10-fold when only those carrying two copies of the long allele were considered (from d = 0.29 for all individuals to d = 0.03). Genetic differential susceptibility means that averaging across all participants is a misleading index of efficacy. The study raises questions about how policy-makers deal with the challenge of balancing equity (equal treatment for all) and efficacy (treating only those whose genes render them likely to benefit) when implementing psychosocial interventions. Trial Registration Current Controlled Trials ISRCTN25664149, In light of genetic information Barak Morgan and colleagues re-analyze data from a randomized controlled trial to explore the genetic susceptibility to a psychosocial intervention., Author summary Why was this study done? It has been shown that individuals with the short form of a gene involved in nerve signaling in the brain are generally sensitive, or “susceptible,” to psychosocial interventions (i.e., they benefit), whereas individuals with the long form of the gene are insensitive, or “nonsusceptible,” deriving little benefit from the same intervention. This study was conducted to investigate whether such a gene × intervention interaction was present in a previously conducted randomized controlled home-visiting intervention trial designed to increase levels of secure maternal-infant attachment at 18 mo of age in a population in South Africa. What did the researchers do and find? Genotyping revealed that 40% of the study sample (n = 89) carried at least one short allele of the serotonin transporter gene, while 60% of the sample (n = 131) carried two long alleles of this gene. We reanalyzed the original maternal-infant attachment results and found that the increase in secure attachment found for the intervention in the original trial (odds ratio = 1.7, effect size d = 0.29) was almost entirely attributable to children with the short form of the gene (odds ratio = 3.86, effect size d = 0.75). For children not carrying the short allele, there was no significant increase in secure attachment with the intervention (odds ratio = 0.95, effect size d = 0.03). Children carrying the short form of the gene whose mothers received the intervention were 3.86 times more likely to be securely attached at 18 mo (84% were secure) than children carrying the short form whose mothers did not receive the intervention (58% were secure). Among children without the short form, the number who were securely attached did not differ based on whether their mothers received the intervention (71% were secure) or not (70% were secure). What do these findings mean? These results indicate the importance of genetic differences when considering the efficacy of psychosocial interventions aimed at improving developmental outcomes in children living in the context of socioeconomic adversity. The findings also raise complex questions regarding spending limited resources implementing costly interventions on individuals who may not benefit because of their genetic makeup and who may comprise the majority of the population (60% in this case), but where these same interventions may nevertheless confer large benefit for a subgroup of genetically susceptible individuals (40% in this case).