To evaluate cofactors for progression of HIV infection, the authors identified 370 men with well-defined seroconversion dates and cofactor data among participants in the San Francisco City Clinic Cohort (SFCCC). Postseroconversion substance use, sexual behavior, and sexually transmitted diseases were assessed using multivariate proportional hazards models. Weekly use of hallucinogens strongly and independently predicted death (relative hazard [RH], 2.59; 95% confidence interval [CI], 1.56-4.28), as well as diagnosis of AIDS; weekly cocaine use also predicted mortality. Receptive anal intercourse with ejaculation was independently associated with mortality risk (RH, 1.45; 95% CI, 1.02-2.04) and AIDS. The associations of accelerated progression with weekly use of recreational drugs and unprotected receptive anal intercourse need to be confirmed in other prospective cohorts.