The association between human immunodeficiency virus (HIV) seropositivity and a history of sexually transmitted diseases (STDs), evidence of STDs on physical examination, and sexual and drug use practices was studied in a population of 2921 intravenous drug users (IVDUs) in Baltimore during 1988 and 1989. Overall, 24.1% were HIV-seropositive at baseline, and 60% reported a history of an STD. A significant association was found between HIV seropositivity and a history of syphilis (P = .04); both were more frequent among homosexual/bisexual men than among heterosexual IVDUs. In multivariate analysis, a history of syphilis was independently associated with HIV seroprevalence in homosexual/bisexual male IVDUs, of whom 90% reported a history of sexual intercourse with women. Cocaine injection was independently associated with HIV seropositivity but not a history of syphilis on multivariate analysis. STDs, indicative of unsafe sex practices, are common in this population; efforts are needed to prevent sexual transmission of HIV infection among IVDUs and their sex partners.