We conducted a case-control study to compare illicit substance and erectile dysfunction medication (EDM) use between recently HIV-infected and uninfected men who have sex with men (MSM). Eighty-six recently (previous 12 months) HIV-infected MSM (cases) and 59 MSM who recently tested HIV-negative (controls) completed computer-assisted self-interviews. There were no statistical differences in demographics or number of sexual partners by HIV status. Cases were more likely than controls to report methamphetamine or nitrite use, but not EDM, gamma hydroxybutyrate, 3,4 methylenedioxymethamphetamine, cocaine, or marijuana use, in the previous 12 months and with their last three sexual partners in multivariate logistic regression models. Use of nitrites and amphetamine may increase HIV risk among MSM.