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Background In sub-Saharan Africa, individuals infected with HIV who are severely immunocompromised have high mortality (about 10%) shortly after starting antiretroviral therapy (ART). This group also has the greatest risk of morbidity and mortality associated with immune reconstitution inflammatory syndrome (IRIS), a paradoxical response to successful ART. Integrase inhibitors lead to significantly more rapid declines in HIV viral load (VL) than all other ART classes. We hypothesised that intensifying standard triple-drug ART with the integrase inhibitor, raltegravir, would reduce HIV VL faster and hence reduce early mortality, although this strategy could also risk more IRIS events. Methods and findings In a 2×2×2 factorial open-label parallel-group trial, treatment-naive adults, adolescents, and children >5 years old infected with HIV, with cluster of differentiation 4 (CD4) 0.7) and despite significantly greater VL suppression with raltegravir-intensified ART at 4 weeks (343/836 [41.0%] versus 113/841 [13.4%] with standard ART, p < 0.001) and 12 weeks (567/789 [71.9%] versus 415/803 [51.7%] with standard ART, p < 0.001). Through 48 weeks, there was no evidence of differences in mortality (aHR = 0.98 [95% CI 0.76–1.28], p = 0.91); in serious (aHR = 0.99 [0.81–1.21], p = 0.88), grade-4 (aHR = 0.88 [0.71–1.09], p = 0.29), or ART-modifying (aHR = 0.90 [0.63–1.27], p = 0.54) adverse events (the latter occurring in 59 [6.5%] participants with raltegravir-intensified ART versus 66 [7.3%] with standard ART); in events judged compatible with IRIS (occurring in 89 [9.9%] participants with raltegravir-intensified ART versus 86 [9.5%] with standard ART, p = 0.79) or in hospitalisations (aHR = 0.94 [95% CI 0.76–1.17], p = 0.59). At 12 weeks, one and two raltegravir-intensified participants had predicted intermediate-level and high-level raltegravir resistance, respectively. At 48 weeks, the nucleoside reverse transcriptase inhibitor (NRTI) mutation K219E/Q (p = 0.004) and the non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations K101E/P (p = 0.03) and P225H (p = 0.007) were less common in virus from participants with raltegravir-intensified ART, with weak evidence of less intermediate- or high-level resistance to tenofovir (p = 0.06), abacavir (p = 0.08), and rilpivirine (p = 0.07). Limitations of the study include limited clinical, radiological, and/or microbiological information for some participants, reflecting available services at the centres, and lack of baseline genotypes. Conclusions Although 12 weeks of raltegravir intensification was well tolerated and reduced HIV viraemia significantly faster than standard triple-drug ART during the time of greatest risk for early death, this strategy did not reduce mortality or clinical events in this group and is not warranted. There was no excess of IRIS-compatible events, suggesting that integrase inhibitors can be used safely as part of standard triple-drug first-line therapy in severely immunocompromised individuals. Trial registration ClinicalTrials.gov NCT01825031. Trial registration International Standard Randomised Controlled Trials Number ISRCTN 43622374., In the factorial randomised REALITY trial, Sarah Walker and colleagues document outcomes of intensified initial antiretroviral treatment for people with advanced HIV disease., Author summary Why was this study done? Individuals in Africa who are HIV positive and initiating treatment with severe immunosuppression (CD4 < 100 cells/mm3) have high risks of dying shortly after starting treatment. It would be expected that adding an integrase inhibitor (raltegravir) to standard triple-drug antiretroviral therapy for 12 weeks would reduce HIV viral load faster: we wanted to find out whether this would reduce high early mortality. What did the researchers do and find? We randomly allocated 1,805 adults, adolescents, and older children to receive standard antiretroviral therapy with or without 12 weeks of adjunctive raltegravir. We found that the group receiving 12 weeks of adjunctive raltegravir had significantly faster declines in HIV viral load. However, we found no significant difference in deaths within 24 weeks of starting treatment between those receiving adjunctive raltegravir (97/902 [10.9%]) or not (91/903 [10.2%]); nor were there differences in clinical disease progression, immune reconstitution, inflammatory syndrome, or adverse events. What do these findings mean? In this study, we found that intensifying the potency of initial antiretroviral therapy did not reduce early mortality on treatment, providing no support for its widespread use in individuals initiating treatment with severe immunosuppression. However, it also did not increase the rates of clinically important immune reconstitution inflammatory syndrome, suggesting that integrase inhibitors could replace other components of standard first-line antiretroviral therapy safely.