Clinically isolated syndrome (CIS) refers to the initial clinical episode with symptoms suggestive of multiple sclerosis (MS). Due to limited number of long-term follow-up studies, progression pattern from CIS to more advanced stages remains unclear. In the current study, we constructed a Markov model to simulate the natural course of CIS. The model estimated the probabilities of transition from CIS to more advanced disease stages and the duration needed for the progression. The analysis showed: (1) CIS is a solid disease identity: more than 85% of the subjects with a diagnosis of CIS progress to RRMS or more advanced stages within 20 years; (2) the reduction of life expectancy in subjects with CIS is marginal.