CONTEXT Pain and depression are the most common physical and psychological symptoms in primary care, respectively. Moreover, they co-occur 30% to 50% of the time and have adverse effects on quality of life, disability, and health care costs. OBJECTIVE To determine if a combined pharmacological and behavioral intervention improves both depression and pain in primary care patients with musculoskeletal pain and comorbid depression. DESIGN, SETTING, AND PATIENTS Randomized controlled trial (Stepped Care for Affective Disorders and Musculoskeletal Pain SCAMP) conducted at 6 community-based clinics and 5 Veterans Affairs general medicine clinics in Indianapolis, Indiana. Recruitment occurred from January 2005 to June 2007 and follow-up concluded in June 2008. The 250 patients had low back, hip, or knee pain for 3 months or longer and at least moderate depression severity (Patient Health Questionnaire 9 score ≥10). INTERVENTION Patients were randomly assigned to the intervention (n = 123) or to usual care (n = 127). The intervention consisted of 12 weeks of optimized antidepressant therapy (step 1) followed by 6 sessions of a pain self-management program over 12 weeks (step 2), and a continuation phase of therapy for 6 months (step 3). MAIN OUTCOME MEASURES Depression (20-item Hopkins Symptom Checklist), pain severity and interference (Brief Pain Inventory), and global improvement in pain at 12 months. RESULTS At 12 months, 46 of the 123 intervention patients (37.4%) had a 50% or greater reduction in depression severity from baseline compared with 21 of 127 usual care patients (16.5%) (relative risk RR, 2.3; 95% confidence interval CI, 1.5-3.2), corresponding to a much lower number of patients with major depression (50 40.7% vs 87 68.5%, respectively; RR, 0.6 95% CI, 0.4-0.8). Also, a clinically significant (≥30%) reduction in pain was much more likely in intervention patients (51 intervention patients 41.5% vs 22 usual care patients 17.3%; RR, 2.4 95% CI, 1.6-3.2), as was global improvement in pain (58 47.2% vs 16 12.6%, respectively; RR, 3.7 95% CI, 2.3-6.1). More intervention patients also experienced benefits in terms of the primary outcome, which was a combined improvement in both depression and pain (32 intervention patients 26.0% vs 10 usual care patients 7.9%; RR, 3.3 95% CI, 1.8-5.4). CONCLUSION Optimized antidepressant therapy followed by a pain self-management program resulted in substantial improvement in depression as well as moderate reductions in pain severity and disability. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00118430