This is a longitudinal predictive study to examine gender differences in the clinical correlates of risk for opioid misuse among chronic pain patients prescribed opioids for pain. Two hundred seventy-five male and 335 female patients prescribed opioids for chronic noncancer pain were asked to complete a series of baseline questionnaires, including the revised Screener and Opioid Assessment for Pain Patients (SOAPP-R). After 5 months, the subjects were administered a structured prescription drug use interview (Prescription Drug Use Questionnaire; PDUQ) and submitted a urine sample for toxicology assessment. Their treating physicians also completed a substance misuse behavior checklist (Prescription Opioid Therapy Questionnaire; POTQ). At 5-month follow-up, women showed higher scores on the PDUQ (P < .05), whereas men had a higher incidence of physician-rated aberrant drug behavior on the POTQ (P < .05). An item analysis of the SOAPP-R, PDUQ, and POTQ showed that women tended to score higher on items relating to psychological distress, whereas the male patients tended to report having more legal and behavioral problems. These results suggest that risk factors associated with prescription opioid misuse may differ between men and women. PERSPECTIVE: Understanding gender differences in substance abuse risk among chronic pain patients is important for clinical assessment and treatment. This study suggests that women are at greater risk to misuse opioids because of emotional issues and affective distress, whereas men tend to misuse opioids because of legal and problematic behavioral issues.