BACKGROUND: Numerous studies have shown that mild-to-moderate intensity or resistance exercise training improves physical capacities such as, peak oxygen consumption, maximal tolerated power and strength in multiple sclerosis patients. However, few studies have evaluated the effects of high-intensity interval training (HIIT) associated to with resistance training. Only few studies have analyzed difference between men and women before and after combined training. Moreover, the evaluation of exercise between ambulatory multiple sclerosis patients without disability (Expanded Disability Status Score [EDSS] 0-3) and patients with disabilities (EDSS 3.5-5) was not largely published. AIM: The main objective of our study was to determine if HIIT combined with resistance training improved aerobic and strength capacities as well as quality of life in multiple sclerosis patients and if gender and disabilities play a role in these changes. DESIGN: This study was an open-label uncontrolled study. SETTING: The study was performed outside from conventional care facilities and including homebased training. POPULATION: Twenty-six multiple sclerosis patients have completed the program (19 women, 7 men; mean age 44.6±7.9 years, EDSS 2 [0-5]). METHODS: We conducted a 12-week program of high-intensity interval training combined with resistance training at body weight. Peak oxygen consumption, maximal tolerated power, lactates, isokinetic strength of quadriceps and hamstrings (at 90°/s, 180°/s, and 240°/s) and quality of life were evaluated before and after the program. RESULTS: Peak oxygen consumption and maximum tolerated power improved by 13.5% and 9.4%, respectively. Isokinetic muscle strength increased in both quadriceps and hamstrings at each speed, with a rebalancing of strength between the two legs in quadriceps. Quality of life was also enhanced in three domains. Women showed better improvements than men in V̇O2peak, maximal tolerated power, lactates at the end of test, and heart rate peak, strength in both quadriceps and hamstrings mostly at low speed, and quality of life. The two EDSS groups increased V̇O2peak and strength. CONCLUSIONS: Our study has shown that HIIT combined with resistance exercise training induced an improvement in physical capacity and quality of life. Moreover, this study allowed patients, irrespective of their sex or EDSS score, to resume exercise autonomously. CLINICAL REHABILITATION IMPACT: The results of the study showed that aerobic training at moderate intensity is not the single type of training tolerated by multiple sclerosis patients. High-intensity interval training is well tolerated too and can be used in clinical rehabilitation with resistance training, in both men and women with and without disabilities.