OBJECTIVE To evaluate diagnostic outcomes, especially as they relate to reason for referral, of patients referred to a university-based multiple sclerosis (MS) center for possible MS. METHODS Retrospective medical record review of all new patient visits to University of Colorado Multiple Sclerosis Center, Denver, from January 1, 2001, to June 30, 2003. RESULTS Of 281 patients referred to evaluate the possibility of MS, after initial review 33% were diagnosed with MS or possible MS by the McDonald criteria. The rest had other neurological conditions (31.5%), probable psychiatric diagnoses (22.5%), or no clear diagnosis was made (12.5%). Of patients with typical, possible, or atypical demyelinating syndromes, 71%, 27%, and 0%, respectively (P<.001), had MS or possible MS. Of the 63% of patients referred on the basis of clinical symptoms and signs, 46% were diagnosed with MS or possible MS vs 11% of patients referred primarily on the basis of abnormal brain magnetic resonance imaging (MRI) results (P<.001). Of patients referred because of abnormal MRI results who did not have MS or possible MS, 70% had a clear alternative etiology for the abnormal MRI results, including migraine, age older than 50 years, other neurological disease, or hypertension. CONCLUSIONS A significant percentage of patients referred to a university-based MS center have little or no likelihood of having MS, and many have undiagnosed, untreated psychiatric illness or common conditions with abnormal brain MRI results. With respect to the diagnosis of MS, greater training of primary care professionals, neurologists, and radiologists is necessary.