Human immunodeficiency virus (HIV)-seronegative high-risk homosexual men were enrolled in a vaccine feasibility study in three US cities. HIV seroincidence was 2.3/100 person-years (95% confidence interval [CI], 1.7-2.9) over 18 months in 1975 men. After receiving an explanation of HIV vaccine trial design, 37% stated they were "definitely" willing to participate in future trials; seroincidence was 3.7/100 person-years (95% CI, 2.5-4.9) in this subgroup. An additional 57% "might be" or were "probably" willing. Independent predictors of HIV seroconversion in multivariable pooled logistic regression analysis were having a known HIV-seropositive sex partner (odds ratio [OR], 4.5; 95% CI, 2.6-7.8), injection drug use (OR, 3.6; 95% CI, 1.2-10.7), unprotected receptive anal sex (OR, 2.4; 95% CI, 1.4-4.2), condom failure (OR, 2.4; 95% CI, 1.4-4.1), gonococcal/nongonococcal urethritis (OR, 2.3; 95% CI, 1.1-4.7), and age < 25 years (OR, 2.2; 95% CI, 1.2-4.2). Interest in vaccine trials and seroincidence in high-risk homosexual men are sufficiently high to initiate efficacy trials once a suitable candidate vaccine is identified. Risk factors for seroconversion highlight important area for development of ancillary intervention strategies.