Abstract Background As a consequence of the substantial rise in the prescription of opioids for the treatment of chronic noncancer pain, greater attention has been paid to the factors that may be associated with an increased risk for prescription opioid misuse. Recently, a growing number of studies have shown that patients with high levels of catastrophizing are at increased risk for prescription opioid misuse. Objective The primary objective of this study was to examine the variables that might underlie the association between catastrophizing and risk for prescription opioid misuse in patients with chronic pain. Methods Patients with chronic musculoskeletal pain (n=115) were asked to complete the SOAPP-R, a validated self-report questionnaire designed to identify patients at risk for prescription opioid misuse. Patients were also asked to complete self-report measures of pain intensity, catastrophizing, anxiety, and depression. Results Consistent with previous research, we found that catastrophizing was associated with an increased risk for prescription opioid misuse. Results also revealed that the association between catastrophizing and risk for opioid misuse was partially mediated by patients’ levels of anxiety. Follow-up analyses, however, indicated that catastrophizing remained a significant ‘unique’ predictor of risk for opioid misuse even when controlling for patients’ levels of pain severity, anxiety and depressive symptoms. Discussion Discussion addresses the factors that might place patients with high levels of catastrophizing at increased risk for prescription opioid misuse. The implications of our findings for the management of patients considered for opioid therapy are also discussed.