This study examined patterns of drug use among gay men and other men who have sex with men (MSM) to identify sub-categories of men whose drug use and sexual behavior place them at especially high risk for HIV. A latent class analysis of a sample of MSM yielded a four-class model with two distinct high drug use sub-groups: one whose drug use concentrated on “sex-drugs” (SDU); and a distinct polydrug use class that showed higher probabilities of using all other drugs assessed. Comparative follow-up analyses indicated the SDU group was also more likely to engage in particular potentially high-risk sexual behaviors, be older, and to be HIV positive. Implications of distinguishing between patterns of drug use for HIV-risk prevention efforts with MSM are discussed.