Objective: To describe the pattern of development of incidence of multiple sclerosis (MS) over 60 years in Denmark with age-period-cohort analyses and seasonality of birth. Methods: Data on virtually all patients with onset of MS have since 1950 been prospectively recorded and kept in the Danish Multiple Sclerosis Registry with multiple sources of notification. Annualized incidence rates per 100,000 were directly standardized to the European Standard Population. Results: We have registered 19,536 cases with clinical onset of confirmed MS in Denmark from 1950 to 2009. From the 1950-1959 to the 2000-2009 onset period, incidence more than doubled in women, with an increase from 5.91 (95% confidence interval [CI]: 5.60-6.24) to 12.33 (95% CI: 11.91-12.75) per 100,000 per year compared with a modest 24% increase in men from 4.52 (95% CI: 4.24-4.81) to 6.08 (95% CI: 5.79-6.38). With age at onset of 50 years and older, incidence increased with a factor 4.30 in women and 2.72 in men. The female/male sex ratio increased over time and with year of birth. Age-period-cohort analysis revealed a significant birth cohort effect in addition to the age and period effect. We found no statistically significant seasonality of births. Conclusion: The incidence of MS has doubled in women, most pronounced with late onset, and has only modestly increased in men. Lifestyle changes in the female population that could include fewer childbirths, increased occurrence of obesity, and increased cigarette consumption may have a role.