Background: Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system, which is accompanied by significant disabilities. Although there are some published data regarding the epidemiological features of MS in other parts of Iran, scarce data are available about the prevalence and demographic characteristics of MS in Fars province. The current study aimed to address the prevalence and incidence rate of MS as well as the temporal trend of the disease in Fars province, southern Iran. Methods: This historical retrospective cohort study was carried out in Fars Multiple Sclerosis Society affiliated with Shiraz University of Medical Sciences. All the consecutive patients who fulfilled 2010 McDonald criteria for definite MS were included in the study. The patients’ gender, age at time of diagnosis, education, and clinical course were recorded. The prevalence and incidence rates were also calculated.Results: This study was conducted on 3,354 patients. Among the patients, 2,689 (80.2%) were female and 665 (19.8%) were male. The female/male ratio was 4.04. The point prevalence rate of the disease was 72.1/100,000 persons in October 2013. This index was 116.5 per 100,000 persons in females (95% CI: 113.4-119.6) and 28.3 per 100,000 persons in males (95% CI: 26.8-29.9). The mean annual incidence rate was 5.2/100,000 from 2002 until 2012. Conclusion: Considering Kurtzke classification, Fars is a high-risk area for MS and women are affected more compared with men. Moreover, the incidence rate sharply increased in the last decade.