Depression, a common problem in multiple sclerosis (MS), is generally associated with poorer quality of life (QOL). However, it is unclear whether treating depression also extends to better perceived QOL. Understanding QOL in MS has been limited by narrow definitions and exclusive focus on symptomology, with little emphasis on positive aspects of QOL. This study examined the impact of treating depression on QOL in 60 patients with a relapsing form of MS and moderate to severe depression, who were randomly assigned to one of three validated 16-week treatments for depression: individual cognitive-behavioral therapy, group psychotherapy, or sertraline. QOL was measured by the MSQOL-54, a version of the SF-36 adapted for MS, and Ryff's scales of psychological well-being, which measure positive attitudes and functioning. Depression and QOL were measured at baseline and immediately following treatment completion. Controlling for baseline neurological impairment and baseline QOL scores, regression analyses showed treating depression was significantly associated with improvements in the MSQOL-54 scales (R2s = 0.19-0.55, p < 0.001) and in four of the six scales of psychological well-being: environmental mastery (R2 = 0.13, p < 0.001), positive relations (R2 = 0.08, p < 0.001), purpose in life (R2 = 0.16, p < 0.001), and self-acceptance (R2 = 0.26, p < 0.001). Findings suggest treating depression influences both the negative and positive aspects of QOL and underscore the importance of examining QOL with two complementary approaches.