| Diagnosis of multiple sclerosis (MS) can be challenging, and misdiagnosis remains a persistent problem with considerable consequences for patients and health-care systems. Common syndromes are frequently mistaken for MS. Misapplication of MS diagnostic criteria in patients with abnormal radiographic findings and clinical presentations that are atypical for MS is a frequent cause of misdiagnosis. Delays in diagnosis of MS and initiation of disease-modifying therapy (DMT) are associated with an increased risk of disability, putting pressure on physicians to make therapeutic decisions for patients whose diagnosis remains uncertain. DMT is associated with unnecessary risks and morbidity in misdiagnosed patients. This tension between the benefits of an early diagnosis and the risk of misdiagnosis is a pressing problem. For patients who present with brain MRI abnormalities and clinical syndromes that are atypical for MS, strict adherence to MS diagnostic criteria and further clinical, laboratory and radiographic evaluation is prudent and likely to clarify a diagnosis.