To study the prevalence of and factors associated with the use of alcohol and nonprescription drugs by HIV-seropositive men who have sex with men (MSM) and to describe variations in alcohol and nonprescription drug use by geographic region, we analyzed data from a multistate, population- and facility-based interview study conducted in 12 U.S. states and metropolitan areas. Among 9735 MSM with HIV infection or AIDS who completed a 45-minute interview, nearly one third reported possible alcohol abuse. Large proportions of MSM also reported the use of marijuana (51%), noninjected cocaine (31%), and crack cocaine (16%) in the 5 years before the interview. Smaller proportions of MSM reported ever having injected cocaine (13%), stimulants (8%), and heroin (8%). Results of logistic regression indicated that in the 5 years before interview, white MSM were significantly (p < .01) more likely than referent (mostly Hispanic) MSM to report use of hallucinogens, marijuana, nitrites, noninjected amphetamines, and diazepam; black MSM were significantly more likely than referent MSM to report use of noninjected crack cocaine. Use of injected stimulants was significantly associated with white race versus referent MSM, and residing in the West versus East. The prevalence of alcohol and drug use among HIV-seropositive MSM is high, and prevalences and types of substance use differ by region and racial/ethnic group. To prevent HIV transmission in this population, health departments and community-based organizations must understand the unique local patterns of substance use to develop effective substance abuse prevention and treatment programs.