Previous studies have shown that use of complementary and alternative medicine (CAM) is prevalent among HIV-infected persons, but have focused primarily on men who have sex with men. To determine factors associated with CAM use in an inner city population, individuals (n = 93) recruited from two established cohort studies were interviewed between October and November 2004. The interview assessed the use of dietary supplements and other CAM therapies, reasons for CAM use, and use of prescription medications. Study participants were 52% male and 47% HIV infected. Median age was 50 years, and 60% reported illicit drug use ever. CAM use during the prior 6 months was reported by 94%, with 48% reporting daily use of a dietary supplement. Vitamin C, vitamin E, and soy were used more often by HIV-infected than uninfected persons (p < 0.05). Prevention of illness was the most common reason for dietary supplement use (27%). HIV-infected persons were more likely than uninfected persons (95% versus 67%) to report use of both dietary supplements and prescription medications within the past 6 months (p < 0.001). In multivariate analysis, HIV infection (odds ratio [OR] 3.1, CI 1.3, 7.7) was the only factor associated with daily dietary supplement use whereas gender, race/ethnicity, working in the last year, homelessness, and financial comfort were not associated. CAM use among persons with or at risk for HIV infection due to drug use or high-risk heterosexual behaviors is common, and is used almost exclusively as an adjunct and not an alternative to conventional health care.