OBJECTIVE: We tested the safety, feasibility, and effectiveness of blood flow restriction-empowered low-intensity interval walking exercise (BFR-W) compared with conventional intensive overground walking (CON-W) at improving gait speed and functional capacity in patients with multiple sclerosis (MS) and severe gait disabilities. METHODS: 24 patients (58 ± 5 years; 7 males) with progressive MS (Expanded Disability Status Scale 5.5 - 6.5) were randomized to receive 12 rehabilitation sessions over 6 weeks. The BFR-W group (n = 12) performed interval walking (speed paced by a metronome that increased weekly) with BFR bands at the thighs. The CON-W group (n = 12) received physiotherapist-assisted overground walking therapy. The primary outcome was gait speed, measured by the timed 25-foot walk test. Secondary outcomes included walking endurance, balance, strength, fatigue, and quality of life. The measurements were collected at baseline, at the end of training, and a 6-week follow-up. RESULTS: The two groups did not present any baseline difference. BFR-W group safely walked without limitations due to sleeve compression, with lower increase in perceived exertion (RPE) (P < .001) and heart rate (P = .031) compared with the CON-W. Gait speed improved significantly in both groups (BFR-W + 13%; CON-W + 5%) with greater increases in the BFR-W group at end of the training (P = .001) and at the follow-up (P = .041). Most of the secondary outcomes significantly improved in the two groups, without between-group differences. CONCLUSIONS: Slow interval walking with moderate BFR to the lower limbs was superior to overground walking in improving gait speed in patients with MS with a lower training load and a more durable clinical benefit.