Background and Objective: For decades, stress has been postulated as a risk factor for multiple sclerosis (MS) relapses. Because of conflicting results in previous studies we conducted a prospective study to investigate this relationship in a less studied, Middle Eastern population. Methods: In this prospective study, 57 Iranian MS patients were followed trimonthly for 12 months. Possible stressful events (measured with validated Persian version of Paykel’s questionnaire) and quality of life (measured with validated Persian version of the Multiple Sclerosis Impact Scale questionnaire) were assessed in successive visits in addition to other variables. Relapses were enquired and confirmed clinically by a Neurologist. Main analysis was done by use of Mixed Generalized Linear Model. Results: Mean age of the participants was 33.5±7.4 years, 81% were females, and all were receiving interferons. Number of stressors, not the stress severity measures, reached near significance in predicting relapses (p=0.054), and showed a trend towards significance in predicting severe relapses (p=0.082). Education and number of previous relapses were the only variables that had a near significance interaction with number of stressors in its association with MS relapse. This association was only significant among subjects with less than college education (P=0.008) and subjects with more than 2 relapses (p=0.038). Conclusion: Number of stressors, not their severity, was associated with MS relapses among Iranian patients. This association had interaction with education and history of previous relapses; it was significant only among lower educated patients or patients with more prior relapses.