Obesity is a health problem that can exacerbate the symptoms of multiple sclerosis (MS). In the current study, we aimed to investigate the effectiveness of a short-term exercise program on fatigue, depression, anxiety, and walking performance in normal-weight and overweight patients with MS (PwMS). Sixty-two PwMS were divided into groups according to their BMI (BMI normal/BMI high). Also, they were all included in the exercise program. The participants took a moderate-intensity walking program 5 days a week for 4 weeks, including 30 min between 5 min of warm-up and 5 min of cooling periods. Also, patients underwent breathing, posture, flexibility, and stretching exercises for 4 weeks. Fatigue, depression, anxiety, 6-minute walking test (6MWT), and BMI were measured before and after the 4 weeks. After the exercise program, there were statistically significant improvements in fatigue, depression, anxiety, and the 6MWT. However, no relation could be detected between the examined variables and BMI. All patients participated effectively in the exercise program, regardless of BMI. The results obtained from this study support that a short-term exercise program is an effective therapeutic intervention, unrelated to BMI, in improving fatigue, depression, anxiety, and walking performance in PwMS.Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.