Abstract Background There is little information about risk acceptance of multiple sclerosis (MS) patients to various MS therapies. Objective To determine MS patients׳ tolerance to risky therapies and identify associated characteristics. Methods MS patients from the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry׳s online cohort were invited to complete questionnaires on decision making and risk tolerance (RT) to two therapeutic scenarios: a theoretical cure for MS CureMS, with permanent reversal of all MS symptoms but a risk of immediate painless death; and natalizumab NAT, a real-life scenario with benefits and risks as defined by Phase III trial results. Results The median RT for both scenarios was 1:10,000; 15–23% of respondents were not willing to take any risk for their MS therapy. Participants with greater disability or not taking any MS therapy showed a greater RT, while females and those caring for dependents had a lower RT. Females and older age were predictors of lower RT, while increasing disability and greater blunting attitude with respect to information seeking behavior were predictors of higher RT. Conclusion MS patients displayed a wide range of RT for MS therapies. Our study identified gender, age, disability and information seeking behavior to be associated with RT.