We studied a cohort of 496 patients who had multiple sclerosis (MS) for at least 10 years. Ten years after disease onset, 151 had benign MS defined as an Extended Disability Status Scale (EDSS) ≤3. Between benign and non-benign patients we compared gender, age at clinical onset, relapsing–remitting or primary progressive, symptoms at onset, recovery from first relapse, time between first and second relapse, number of relapses in the first 5 years, use of immunomodulatory drugs, and EDSS scores at 2, 5 and 10 years. A multivariate regression analysis showed that a relapsing–remitting course, a low EDSS score at 5 years, and a low number of relapses in the first 5 years were predictive for benign MS at 10 years. Other factors had no additional value. Thirty-five of the 51 patients (69%) with benign MS at 10 years were still benign at 20 years. A low 10-year EDSS score was the only clinical variable associated with a benign course at 20 years. Our results suggest that within the first 5 years from onset it is not possible to predict a benign course. Disease course, EDSS score and relapse rate at 5 years are predictors for benign MS at 10 years.