Background: Mediated and moderated processes that lead to intervention efficacy may underlie results of trials ruled as nonefficacious. The overall purpose of this study was to examine such processes to explain the findings of one of the largest, rigorously conducted behavioral intervention randomized controlled trials, EXPLORE. Methods: Four thousand two hundred ninety-five HIV-negative men who have sex with men (MSM) in the United States were randomized in a 2-armed trial. Participants completed follow-up and an HIV test every 6 months up to 48 months. We used multiple and causal mediation analyses to test 5 mediators, including safer sex self-efficacy and condomless receptive anal sex with HIV-positive or status-unknown partners on our primary outcome (HIV seroconversion). We also examined whether intervention effects on the mediators would be moderated by robust correlates of HIV among MSM, including stimulant use. Results: There were significant effects of the intervention on all hypothesized mediators. Stimulant use moderated the effect on condomless receptive anal sex In stratified multiple mediation models, we found that among MSM with low stimulant use, the intervention significantly prevented HIV by reducing condomless receptive anal sex with HIV-positive or status-unknown partners. Among MSM with higher stimulant use, there were no indirect effects of the intervention on HIV through any of the hypothesized mediators. Conclusion: The results suggest that the null effect found in the original EXPLORE trial might have occurred as a function of previously unexplored mediated and moderated processes. This study illustrates the value of testing mediated and moderated pathways in randomized trials, even in trials ruled out as nonefficacious.