To examine factors associated with HIV infection in injecting drug users (IDU), the independent and interactive effects of potential risk factors, and geographic differences in risk factors. IDU entering methadone treatment in New York City, Asbury Park and Trenton in New Jersey, Baltimore and Chicago between February 1987 and December 1991 were interviewed using a standard questionnaire and tested for HIV antibodies (n = 4584). Associations of HIV serostatus with race/ethnicity, other demographic characteristics, and injecting and sexual risk behaviors were assessed by logistic regression analyses. African Americans were at increased risk for HIV in four of the five cities, and Puerto Ricans in two cities. Injection in shooting galleries and 'speedball' injection emerged as behavioral variables highly associated with HIV, although interaction of these variables indicates that each variable contributes to HIV risk only in the absence of the other behavior. Geographic differences in HIV risk factors and the interaction of 'speedball' and shooting gallery use suggest that multiple HIV risk models are needed that reflect seroprevalence rates, variation in risk behaviors, and the social context of risk behaviors. Increased risk among racial/ethnic minorities independent of risk behaviors, suggests the need to examine further potential social and environmental factors, such as the social networks in which injecting and sexual behaviors occur, HIV seroprevalence within these networks, and the locales in which risk behaviors occur.