Despite reports that influenza vaccination appears to be safe in multiple sclerosis there is uncertainty which patients may benefit from it. By using a questionnaire we compared the effects of influenza illness (1995-1996 season) and influenza vaccination (autumn of 1996) on neurologic symptoms in patients with multiple sclerosis registered in the Groningen Multiple Sclerosis Data Bank. No clinically relevant effects were reported in 53 patients with primary progressive multiple sclerosis, either following vaccination or the illness. In a group of 180 patients with relapsing multiple sclerosis, an exacerbation occurred within the following 6 weeks in 33% after influenza illness, whereas it occurred in only 5% after vaccination. The exacerbation rate following influenza illness was significantly higher regardless of whether patients were essentially restricted to wheelchair or not. Because of a substantial greater risk of relapse after influenza illness than after vaccination, annual influenza vaccination should be offered routinely to all patients with relapsing multiple sclerosis.