This study examines associations between prescription opioid misuse and demographics, substance use, sexual behavior, and related health and social problems. Baseline data were collected between 2008 and 2010 from 515 high risk men who have sex with men (MSM), ages 18–55, in the Miami-Ft. Lauderdale metropolitan area who reported heavy substance use and HIV risk in the past 90 days. Prescription opioid misuse was associated with other substance use, drug injection, substance dependence, and history of arrest. Implications, limitations, and directions for future study are discussed.