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Background Although there is mounting evidence demonstrating beneficial effects of community health workers (CHWs), few studies have examined the impact of CHW programs focused on preventing infectious diseases in children through behavior changes. We assessed the preventive effects of community health volunteers (CHVs), who receive no financial incentive, on child diarrhea and fever prevalence in Ghana. Methods and findings We conducted a cluster-randomized controlled trial in 40 communities in the Volta Region, Ghana. Twenty communities were randomly allocated to the intervention arm, and 20 to the control arm, using a computer-generated block randomization list. In the intervention arm, CHVs were deployed in their own community with the key task of conducting home visits for health education and community mobilization. The primary outcomes of the trial were diarrhea and fever prevalence at 6 and 12 months among under-5 children based on caregivers' recall. Secondary outcomes included oral rehydration treatment and rapid diagnostic testing for malaria among under-5 children, and family planning practices of caregivers. Generalized estimating equations (GEEs) with a log link and exchangeable correlation matrix were used to determine the relative risk (RR) and 95% confidence intervals (CIs) for diarrhea, fever, and secondary outcomes adjusted for clustering and stratification. Between April 18 and May 4, 2015, 1,956 children were recruited and followed up until September 20, 2016. At 6 and 12 months post-randomization, 1,660 (85%) and 1,609 (82%) participants, respectively, had outcomes assessed. CHVs' home visits had no statistically significant effect on diarrhea or fever prevalence at either time point. After a follow-up of 12 months, the prevalence of diarrhea and fever was 7.0% (55/784) and 18.4% (144/784), respectively, in the control communities and 4.5% (37/825) and 14.7% (121/825), respectively, in the intervention communities (12-month RR adjusted for clustering and stratification: diarrhea, RR 0.73, 95% CI 0.37-1.45, p = 0.37; fever, RR 0.76, 95% CI 0.51-1.14, p = 0.20). However, the following were observed: improved hand hygiene practices, increased utilization of insecticide-treated bed nets, and greater participation in community outreach programs (p-values < 0.05) in the intervention group. In a post hoc subgroup analysis, the prevalence of diarrhea and fever at 6 months was 3.2% (2/62) and 17.7% (11/62), respectively, in the intervention communities with [greater than or equal to]70% coverage and a [greater than or equal to]30-minute visit duration, and 14.4% (116/806) and 30.2% (243/806) in the control communities (RR adjusted for clustering, stratification, baseline prevalence, and covariates: diarrhea, RR 0.23, 95% CI 0.09-0.60, p = 0.003; fever, RR 0.69, 95% CI 0.52-0.92, p = 0.01). The main limitations were the following: We were unable to investigate the longer-term effects of CHVs; the trial may have been underpowered to detect small to moderate effects due to the large decline in diarrheal and fever prevalence in both the intervention and control group; and caregivers' practices were based on self-report, and the possibility of caregivers providing socially desirable responses cannot be excluded. Conclusions We found no effect of CHVs' home visits on the prevalence of child diarrhea or fever. However, CHV programs with high community coverage and regular household contacts of effective duration may reduce childhood infectious disease prevalence. Trial registration International Standard Randomised Controlled Trial Registry, ISRCTN49236178., Author(s): Yeunji Ma 1, Christopher R. Sudfeld 2, Heunghee Kim 3, Jaeeun Lee 4, Yinseo Cho 4, John Koku Awoonor-Williams 5, Joseph Kwami Degley 5, Seungman Cha 2,6,* Introduction Globally, [...]