Objectives:To examine the association of exposure to sociodemographic, environmental, and lifestyle risk factors during adolescence with the development of multiple sclerosis (MS).Methods:We conducted a case-control study between October 2017 and January 2018 at King Fahd General Hospital (KFH) in Madinah, Saudi Arabia. Data were collected by direct physician-subject interviews. We utilized a questionnaire modified from the environmental risk factors in multiple sclerosis questionnaire (EnvIMS-Q). Chi-square tests were used to examine associations of selected risk factors with the development of MS, a p-value of <0.05 was considered significant.Results:A total of 80 cases and 160 controls were enrolled into the study. Smoking during adolescence significantly increased the risk of MS, with an adjusted odds ratio (AOR) of 4.165, and a 95% confidence interval (CI) of 1.449-11.974. Large body size, assessed using a figure rating scale, also increased the risk of MS (AOR=8.970, 95% CI=1.032-77.983), as well as a history of measles infection (AOR=3.758, 95% CI=1.455-9.706). Furthermore, exposure to sunlight during the weekend for more than 4 hours/day decreased the risk of MS (AOR=0.063, 95% CI=0.006-0.654), so did the consumption of fish for more than once per week (AOR=0.206, 95% CI=0.055-0.773).Conclusion:The risk of developing MS is significantly increased by exposure during adolescence to smoking, a history of measles infection, and large body size (obesity).