Multiple sclerosis is the most frequent demyelinating disease in adults. It is characterized by demyelination, inflammation, gliosis and a variable loss of axons. Clinically and histologically, it shares features with other demyelinating and/or inflammatory CNS diseases. Diagnosis of an inflammatory demyelinating disease can be challenging, especially in small biopsy specimens. Here, we summarize the histological hallmarks and most important neuropathological differential diagnoses of early MS, and provide practical guidelines for the diagnosis of inflammatory demyelinating diseases.