The purpose of this study was to examine the role of catastrophizing as a mediator and moderator between life stress and depression in a sample of workers' compensation patients with chronic musculoskeletal pain. Pain intensity, life stress (especially work and financial stress), and catastrophizing contributed significantly to depression. Catastrophizing was found to be partially mediating the relationship between life stress and depression and a moderator between social stress and depression. The results supported the role of catastrophizing as a cognitive vulnerability-stress factor related to depression in chronic pain patients. Screening for life stress and intervening early to prevent catastrophizing from occurring in the workers' compensation rehabilitation process may reduce psychosocial distress and enhance the overall effectiveness of rehabilitation programming for workers' compensation patients with chronic pain.