Late onset multiple sclerosis (LOMS), defined as the first presentation of clinical symptoms in patients over 50, is not a rare phenomenon as previously thought, since the prevalence ranges between 4% and 9.6% in different studies. The course of the disease is often primary progressive and pyramidal or cerebellar involvement is observed in 60%-70% of the patients at presentation. LOMS is usually associated with a faster progression to disability compared to young adult multiple sclerosis (MS) patients. Moreover in patients over 50, MS variants and atypical forms which present a difficult diagnostic problem, may be frequently encountered. The differential diagnosis may be sometimes difficult and includes cerebro-spinal vascular syndromes, hypertension-related disorders, compressive myelopathies, primary or secondary vasculitis, metabolic diseases, degenerative and nutritional syndromes. Clinical characteristics, magnetic resonance imaging (MRI) pattern of abnormalities, evoked potential studies and cerebrospinal fluid (CSF) oligoclonal band analysis are of high diagnostic yield in LOMS patients, but expertise in interpreting their results is strongly required.