Objective: Prescription drug misuse (PDM) is an emerging epidemic in the U.S. Homeless men experience higher risk for substance misuse and associated health problems and are particularly vulnerable to PDM and its negative health consequences. Methods: Participants were a representative probability sample of 305 heterosexually-active homeless men interviewed from meal programs in the Skid Row region of LA. Interviews assessed demographics, substance use, mental health and social networks. Logistic regression examined correlates of PDM. Results: 26% of the study population reported PDM in the past year. PDM was more likely among homeless men suffering from PTSD (OR = 2.41, 95% CI: 1.03—5.61) and among those with more substance-using social network members (OR = 1.07, 95% CI: 1.01—1.14). Decreased PDM was associated with good health (OR = 0.34, 95% CI: 0.16—0.75). Conclusions: The prevalence of PDM is higher among the homeless men in this study than in the general population. Correlates of PDM included PTSD and poor health, suggesting that homeless men may use PDM to self-medicate. PDM was also associated with increased substance-using social network alters. Physical and mental health and social context are important aspects to consider in prevention efforts to reduce PDM among homeless men.