Background Homeless men may be at particular risk for the negative health effects of substance use. This cross-sectional study investigates the individual and personal network risk factors associated with substance use in this vulnerable population. Methods Participants were a representative probability sample of 305 heterosexually active homeless men interviewed from meal programs in the Skid Row region of Los Angeles, CA. Interviews assessed individual, personal network, and substance use characteristics. Logistic regression examined individual and personal network predictors of the three most prevalent substances. Results In the past 6 months, the three most prevalent substances were marijuana (56%), crack (40%), and alcohol to intoxication (38%). The mental health status of homeless men was associated with substance use, with PTSD more common among those who used crack. Riskier networks (comprised of a larger proportion of drug users) were associated with marijuana use, and normative social ties (family, employed and school/work contacts) were associated with a decreased likelihood of crack use. Conclusions Mental health problems and riskier personal networks are associated with homeless men's substance use. These findings underscore the importance of interventions that focus on improving mental health, mitigating the drug-using norms of personal networks, and helping men to maintain contact with normative, low-risk alters. Mental health care and peer-based, network interventions to reduce substance use should be a priority for heterosexually active homeless men.