The risk groups of men who have sex with men and injection drug users (IDUs) together account for 90% of all male AIDS cases. The extent to which each risk behavior contributes to seroprevalence among IDUs has not been determined and is critical for intervention development. Analysis of data on sexual orientation, injection drug use, and HIV serostatus was undertaken in a multisite study of 3002 male drug injectors and crack smokers recruited for HIV prevention projects. Overall HIV seroprevalence was 8.4%; 57.1% for gay men, 25.4% for bisexual men, and 7.4% for heterosexuals (p = 0.001). Logistic regression analyses indicated being gay (OR = 24.08) and coming from an area where seroprevalence is high among IDUs (OR = 4.07) were the best predictors of serostatus. Ever having injected was significant only in interaction with moderate (OR = 3.09) or high (OR = 4.71) IDU seroprevalence areas. Among this multisite sample of drug users, being a gay drug user is the strongest predictor of serostatus. Drug injection is significant only in areas of moderate or high seroprevalence among injectors. This indicates the importance of targeted outreach and intervention efforts.