We examined how drugs, high-risk sexual behaviors, and socio-demographic variables are associated with recent HIV infection among men who have sex with men (MSM) in a case-control study. Interviewers collected risk factor data among 111 cases with recent HIV infection, and 333 HIV-negative controls from Chicago and Los Angeles. Compared with controls, cases had more unprotected anal intercourse (UAI) with both HIV-positive and HIV-negative partners. MSM with lower income or prior sexually transmitted infections (STI) were more likely to be recently HIV infected. Substances associated with UAI included amyl nitrate ("poppers"), methamphetamine, Viagra (or similar PDE-5 inhibitors), ketamine, and gamma hydroxybutyrate (GHB). Cases more frequently used Viagra, poppers, and methamphetamine during UAI compared with controls. In multivariate analysis, income, UAI with HIV-positive partners, Viagra, and poppers remained associated with recent HIV seroconversion. Better methods are needed to prevent HIV among MSM who engage in high-risk sex with concurrent drug use.