OBJECTIVE: Pain is prevalent in patients with depression. The purpose of this study was to determine the impact of pain on depression treatment outcomes. METHODS: Data was analyzed from a randomized controlled trial comparing a collaborative care intervention to usual care for the treatment of depression in 60 primary care practices. A total of 405 patients with either current major depressive disorder or dysthymia were enrolled, and assessed at baseline, 3, and 6 months. Main measures included the 20-item Hopkins Symptom Check List (HSCL-20) depression score, and the SF-36 pain interference score. RESULTS: Pain severe enough to produce at least moderate interference with daily activities was present in 42% of depressed patients at baseline. Pain outcomes did not differ between intervention and control groups but improved similarly in both over time. However, pain was still at least moderately severe in 32% of patients at 6 months. Both baseline pain and the amount of pain improvement over time were associated with depression remission and response rates. In a multivariate model controlling for age, gender, and medical co-morbidity, depression severity increased with higher pain interference and decreased with the passage of time (p<.0001 for both). There was also a significant pain by time by treatment group interaction (p=.027). The beneficial effects of collaborative care on depression outcome persisted (p=.049) even after controlling for pain interference, time, covariates, and interaction effects. CONCLUSIONS: Pain has a strong negative impact on the response of depression to treatment. Recognizing and optimizing the management of comorbid pain that commonly coexists with depression may be important in enhancing depression response and remission rates.