By applying the behavioral theory of Lewinsohn et al. [1985. An integrative theory of depression. In: S. Reiss, & R. R. Bootzin (Eds.), Theoretical issues in behavior therapy (pp. 331-359). San Diego, CA: Academic Press.] to multiple sclerosis (MS), it was hypothesized that physical disability, fatigue, and psychosocial dysfunction would be significantly predictive of depressed mood in MS patients. Seventy-six MS patients completed the following measures: the Sickness Impact Profile (SIP), the Fatigue Impact Scale (FIS), and the mood subscale from the Chicago Multiscale Depression Inventory (CMDI). Structural equation modeling revealed that physical disability and fatigue were indirectly predictive of depressed mood via their effects on recreational functioning. Fatigue also had a direct effect on mood. If reductions in recreational activities actually cause decrements in mood, depressed mood in MS may be treatable by helping patients identify recreational activities that they can enjoy regardless of physical or fatigue-related difficulties.