OBJECTIVE The incidence of multiple sclerosis (MS) is not well known in Iran. This study was conducted to estimate the trends in annual MS incidence in Iran from March 21, 2010, to March 20, 2016. METHODS Longitudinal study. METHODS In this longitudinal study, data for all MS patients fulfilling McDonald criteria were obtained from a national registry, coordinated by the Ministry of Health (MOH). In Iran, all MS patients are eligible to receive public care and treatment services based on their records in this registry, and thus nearly all MS patients are registered in this database. The annual incidence rates were calculated based on year of diagnosis and were standardized using the World Health Organization (2000-2025) population as a standard. RESULTS In this registry, 36,287 (8202 [22.6%] males and 28,085 [77.4%] females) confirmed MS cases were registered by the MOH between 2010 and 2016. The female-to-male ratio was 3.11. The mean age of patients was 31.6 ± 0.9 years at the time of diagnosis. It was 31.3 ± 0.8 and 32.3 ± 0.9 for females and males, respectively. Overall incidence rate was 6.7/100,000 population (95% confidence interval [CI]: 6.2-7.2); 10.5 and 3.0 in females and males, respectively. The age-adjusted incidence rates increased significantly from 4.4 (95% CI: 4.3-4.6) in 2010 to 5.8 (95% CI: 5.7-6.0) in 2016, with its peak at 6.5 (95% CI: 6.3-6.6) in 2014. CONCLUSIONS This study revealed that Iran is a high-risk area for MS disease and that MS incidence and female-to-male ratio are more or less comparable with the dominant patterns in developed countries. Also, this study showed that the incidence trend of MS in Iran is similar to regional and global observed patterns.