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This analysis of correlates of the risk of HIV-1 infection in the RV144 vaccine trial identifies hypotheses for improving efficacy. The data indicate key roles of V1V2 (variable regions 1 and 2) IgG antibodies and envelope protein (Env) IgA antibodies in modulating infection risk. In clinical trials that show the efficacy of a vaccine, the identification of immune responses that are predictive of trial outcomes generates hypotheses about which of those responses are responsible for protection. 1 – 3 The RV144 phase 3 trial in Thailand (ClinicalTrials.gov number, NCT00223080) was an opportunity to perform such a hypothesis-generating analysis for a human immunodeficiency virus type 1 (HIV-1) vaccine. 4 Studies involving patients with HIV-1 infection in whom the disease did not progress in the long term have shown that cellular responses control the disease, 5 and passive infusion of neutralizing antibodies prevents infection with chimeric simian–human immunodeficiency virus (SHIV). . . .