Abstract Background As a chronic, disabling disease, multiple sclerosis (MS) has challenged healthcare systems in many ways. MS adversely affects patients’ quality of life and self-efficacy and results in psychological stress. The present study was conducted to investigate the effect of peer education based on Pender’s health promotion model on the quality of life, stress management, and self-efficacy of patients with MS in the south of Iran. Methods The present study was a randomized controlled clinical trial. A total of 90 patients were divided into group A intervention group 45 patients) and group B (control group 45 patients). The intervention was peer education based on Pender’s health promotion model. Data were collected using the MS Quality of Life Scale, the Self-efficacy Scale, and the Stress Management Scale. Data analyses were conducted using SPSS version 22. To analyze the data, we used descriptive statistics. Thus, inferential statistics applied included Chi-square, independent-samples t-test, and Repeated measures (ANOVA). The significance level was considered p