Mortality in patients with multiple sclerosis (MS) is significantly increased compared with the general population. Many questions concerning survival in MS are still unanswered due to the difficulty of comparing information collected at different times and in different geographic areas. The increasing incidence of MS, the improvement in care of the chronically disabled, and different methodologies may explain the lack of coherence among studies' results. Reported times to death from birth and from disease onset/diagnosis are highly variable. Patients older at onset or with primary progressive course have shorter survival; however, data on sex and mortality are contradictory. Changes in sex ratio in MS over time represent one possible explanation. MS is the main cause of death in ≥50% of patients and the incidence of deaths not due to MS varies among countries. Particularly, suicide is substantially increased in patients with MS, and, despite its varying incidence, mainly due to “cultural bias,” it should be considered an MS-related cause of death. Recent results of the long-term follow-up study of interferon-β-1b demonstrated a significant reduction of mortality among treated patients. Notwithstanding its long latency, mortality is therefore an unambiguously valid long-term outcome in randomized controlled trials. It usefully combines the net impact of treatment efficacy on longevity and adverse events, which may reduce it.