Standardized interview techniques, diagnostic criteria, and rating scales were used to assess 50 moderately disabled multiple sclerosis (MS) patients. Fifty-four percent met lifetime Research Diagnostic Criteria for major depression, with a significant increase in the rate from before to after the onset of MS symptoms. The MS patients were significantly more depressed than other medical patients described in the literature. Major depressions were associated with steroid-treated exacerbations and a history of major depression. Symptoms of depression may be easily confused with those of MS, resulting in inadequate diagnosis and treatment.