IMPORTANCE: Despite the prevalence and the functional, psychological, and economic impact of chronic pain, few intervention studies of treatment of chronic pain in veterans have been performed. OBJECTIVE: To determine whether a stepped-care intervention is more effective than usual care, as hypothesized, in reducing pain-related disability, pain interference, and pain severity. DESIGN, SETTING, AND PARTICIPANTS: We performed a randomized clinical trial comparing stepped care with usual care for chronic pain. We enrolled 241 veterans from Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn with chronic (>3 months) and disabling (Roland Morris Disability Scale score, ≥7) musculoskeletal pain of the cervical or lumbar spine or extremities (shoulders, knees, and hips) in the Evaluation of Stepped Care for Chronic Pain (ESCAPE) trial from December 20, 2007, through June 30, 2011. The 9-month follow-up was completed by April 2012. Patients received treatment at a postdeployment clinic and 5 general medicine clinics at a Veterans Affairs medical center. INTERVENTIONS: Step 1 included 12 weeks of analgesic treatment and optimization according to an algorithm coupled with pain self-management strategies; step 2, 12 weeks of cognitive behavioral therapy. All intervention aspects were delivered by nurse care managers. MAIN OUTCOMES AND MEASURES: Pain-related disability (Roland Morris Disability Scale), pain interference (Brief Pain Inventory), and pain severity (Graded Chronic Pain Scale). RESULTS: The primary analysis included 121 patients receiving the stepped-care intervention and 120 patients receiving usual care. At 9 months, the mean decrease from baseline in the Roland Morris Disability Scale score was 1.7 (95% CI, -2.6 to -0.9) points in the usual care group and 3.7 (95% CI, -4.5 to -2.8) points in the intervention group (between-group difference, -1.9 [95% CI, -3.2 to -0.7] points; P=.002). The mean decrease from baseline in the Pain Interference subscale score of the Brief Pain Inventory was 0.9 points in the usual care group and 1.7 points in the intervention group (between-group difference, -0.8 [95% CI, -1.3 to -0.3] points; P=.003). The Graded Chronic Pain Scale severity score was reduced by 4.5 points in the usual care group and 11.1 points in the intervention group (between-group difference, -6.6 [95% CI, -10.5 to -2.7] points; P=.001). CONCLUSIONS AND RELEVANCE: A stepped-care intervention that combined analgesics, self-management strategies, and brief cognitive behavioral therapy resulted in statistically significant reductions in pain-related disability, pain interference, and pain severity in veterans with chronic musculoskeletal pain. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00386243.