The percentage contribution of each item on the Beck Depression Inventory (BDI) to the total BDI score was compared across patients with multiple sclerosis (MS), patients diagnosed with major depressive disorder, and normal college students. We considered an item to be confounded by MS-related symptoms if its percentage contribution to the total BDI score was significantly greater in the MS group than the major depression and control groups. Items measuring work difficulty, fatigue, and concerns about health met this criterion. These items accounted for 34, 17, and 19% of the total BDI score in the MS, major depression, and control groups, respectively. Using the 18-item BDI (BDI-18) which resulted from excluding the 3 confounded items, MS patients found to be were more depressed than controls but less depressed than the major depression group. The identification of signs of depression not confounded with MS which could be substituted for confounded signs was also discussed.