Objective: Although the effectiveness and risks of multiple sclerosis (MS) therapies are established, relatively little is known about how these benefits and risks are perceived and weighed by patients. This risk−benefit trade-off is important for clinicians, industry, and regulators to consider when determining which therapies to develop, approve for clinical use, and recommend to individual patients. The primary objective of the present study was to describe individual differences in how MS patients weigh risks and benefits when making treatment decisions. Method: Two hundred ninety patients with MS completed tasks assessing their willingness to take a hypothetical disease-modifying therapy (DMT) at varying levels of efficacy, side effect probability, and side effect severity. Patients also completed questionnaires assessing MS knowledge, medication beliefs, health care climate, and disease severity. Results: Patients with a primary progressive course reported increased DMT willingness compared to patients with relapsing–remitting and secondary progressive courses. Patients were less willing to initiate a DMT across a range of efficacies and side effects if they had never taken a DMT, reported more complementary and alternative health beliefs, or reported a history of discontinuing DMTs due to side effects. More MS knowledge was associated with more willingness to initiate a DMT. Conclusions: The results represent an initial step in understanding how patients with chronic disease balance the risks and benefits of medication initiation. Extension of this research may have implications for pharmaceutical development, physician−patient interaction, adherence intervention, and disease education.