There is compelling epidemiological evidence that prior infection with Epstein-Barr virus (EBV) is necessary to develop multiple sclerosis (MS). That people who are EBV-negative are protected from getting MS underpins the primary MS prevention strategy of using a sterilizing EBV vaccine. The mechanism of how EBV causes MS is unknown, but late symptomatic EBV infection, or infectious mononucleosis (IM), is a more significant risk factor than early asymptomatic EBV infection. Preventing IM with an effective EBV vaccine should reduce the incidence of MS and other EBV-associated diseases. Preventing IM at a population level, as a public health initiative, is much more feasible than attempting to target people at high risk of developing MS, such as family members of people with MS.