The present study sought to identify characteristics of HIV-infected MSM that are associated with the use of specific substances and substance abuse in general. Participants were 503 HIV-infected MSM who were receiving primary care. A self-assessment and medical records were used to obtain information about past 3-month alcohol and drug use and abuse, and demographics, HIV-disease stage and treatment, sexual risk, and mental health. Associations of these four domains with substance use and abuse outcomes were examined using hierarchical block-stepwise multivariable logistic regression. Substance use and abuse in the sample was high. Transmission risk behavior was significantly associated with over half of the outcomes. The associations of demographic and HIV-disease stage and treatment variables varied by substance, and mental health problems contributed differentially to almost every outcome. These findings should be considered for designing, implementing, and evaluating substance use programming for HIV-infected MSM.