OBJECTIVE The high seroprevalence of HIV that has been reported among homeless individuals with mental illness indicates an urgent need to examine HIV risk behavior in this population. METHODS Injection drug use and sexual behavior were assessed in comprehensive interviews with 218 homeless mentally ill men in a New York City shelter. First, the proportion of men who had injected drugs was established. Then, among those who had injected drugs, the injection drug use behaviors associated with HIV transmission (i.e., whether they had ever engaged in high-risk behaviors and had ever engaged in risk-reduction behaviors) and their current sexual risk behaviors were examined. RESULTS Fifty (23%) of the 218 men had injected drugs. Among these 50, the great majority had engaged in high-risk behaviors, including sharing needles (66%) and using shooting galleries (64%). Few had engaged in risk-reduction behaviors, such as cleaning needles with bleach (22%) and using a needle exchange program (2%). In the past 6 months alone, the majority of the injection drug users had had unprotected sex with women (48%) or with men (10%). CONCLUSIONS This study documents a high lifetime prevalence of injection drug use in a group of homeless men with mental illness. The men who had injected drugs reported injection drug use and sexual behaviors with high risk of HIV transmission and gave scant evidence of risk-reduction behaviors. These individuals may fall between service systems and may be difficult to reach but, nonetheless, must be included in efforts to prevent transmission of HIV infection.