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There has long been a belief that depression contributes to fatigue in multiple sclerosis (MS) although supporting data are minimal at best. Clinical guidelines for the treatment of fatigue include recommendations for the treatment of depression in the absence of clear empirical support. The goal of this study was to examine the effects of treatment for depression on fatigue in MS.Sixty patients with a relapsing form of MS and moderate to severe depression were randomly assigned to one of three validated 16-week treatments for depression: individual cognitive behavioral therapy, group psychotherapy, or sertraline. Assessments at baseline and treatment cessation included the primary outcome measure, fatigue assessment instrument (FAI), and Beck depression inventory (BDI).The total FAI and the global fatigue severity subscale were significantly reduced over the course of treatment (p values <.02). Other subscales did not change significantly. Secondary analyses showed change in global fatigue severity was associated with change in BDI (p = .03) but change in total FAI was only marginally related to change in BDI (p = .05). These relationships were due entirely to change in mood (p values <.02) and not to change in cognitive or vegetative symptoms (p values >.17).These findings suggest that treatment for depression is associated with reductions in the severity of fatigue symptoms, and that this relationship is due primarily to treatment related changes in mood.