Chronic musculoskeletal pain (CMP) is the most common, disabling, and costly of all pain problems. While evidence exists for the efficacy (albeit modest benefits) of both duloxetine and web-based cognitive behavioral therapy (CBT) as monotherapy, it is time to consider study of treatment components that may complement each other. In addition, given the reported association between patient’s adherence and treatment outcomes, strategies are needed to enhance participant’s motivation to maintain continued use of newly learned pain coping skills from CBT. Using motivational interviewing (MI), a phone based adherence-focused guidance by a nurse clinician could make web-based CBT more effective. The objective of the UH3 application is to determine if combination therapy (duloxetine + web-based CBT) is more effective than duloxetine monotherapy for treating patients with CMP. Given the interactions of biological, behavioral and psychological mechanisms in the pathogenesis of chronic pain, our central hypothesis is that combination therapy will be more effective than duloxetine monotherapy. The objective of this UG3/UH3 application is to conduct a 24-week randomized clinical trial of primary care patients with CMP. In the UH3 trial, 450 participants will be randomized to one of three treatments: (1) combination treatment [duloxetine + web-based CBT] with nurse support, (2) combination treatment without nurse support, and (3) duloxetine monotherapy. This project could optimize pain-related treatment outcomes by combining duloxetine and web-based CBT at the primary care level where most pain patients are managed. Importantly, the use of nurse clinician providing adherence-focused guidance to maintain long term use or practice of pain coping skills (web-based CBT) increases the likelihood that our proposed intervention is scalable.