A diagnostic dilemma exists when clinicians face patients with atypical recurrent symptoms involving both physical and psychologic elements. Multiple sclerosis (MS) represents such a dilemma. Few authors address themselves to the significance of depressive illness as the initial presentation in MS. Three patients hospitalized solely due to recurrent emotional disorders are described. Depressive symptoms predominated. In each case no precipitant for depression was identified, no previous neurologic diagnosis was entertained by clinician or patient, and multiple prior psychotherapeutic interventions were unsuccessful. The episodic nature of the symptoms and poor response to usually effective treatments created a high index of suspicion for central nervous system disease. A diagnosis of MS was made based on subtle neurologic signs, spinal fluid gamma globulin elevations, and abnormalities in neuropsychological testing. Treatment involved integrated psychiatric and medical measures.