Background: Exercise can improve muscle function and mobility in people with multiple sclerosis (MS). However, the effects of exercise training on skeletal muscle oxidative capacity and endurance in people with MS remain unclear, and few studies have evaluated muscle plasticity in people with MS who have moderate-to-severe disability. The present study evaluated the effects of treadmill training on muscle oxidative capacity and muscle endurance and examined the relationship to walking function in people with MS who have moderate-to-severe disability. Methods: Six adults (mean ± SD age, 50 ± 4.9 years) with MS (Expanded Disability Status Scale score, 6.0-6.5) performed treadmill training for 24 minutes approximately twice per week for approximately 8 weeks (16 sessions total) using an antigravity treadmill system. The following measures were taken before and after the intervention phase: muscle oxidative capacity in the medial gastrocnemius using near-infrared spectroscopy after 15 to 20 seconds of electrical stimulation; muscle endurance in the medial gastrocnemius using accelerometer-based mechanomyography during 9 minutes of twitch electrical stimulation in three stages (3 minutes per stage) of increasing frequency (2, 4, and 6 Hz); and walking function using the 2-Minute Walk Test. Results: Mean ± SD muscle oxidative capacity increased from 0.64 ± 0.19 min-1 to 1.08 ± 0.52 min-1 (68.2%). Mean ± SD muscle endurance increased from 80.9% ± 15.2% to 91.5% ± 4.8% at 2 Hz, from 56.3% ± 20.1% to 76.6% ± 15.8% at 4 Hz, and from 29.2% ± 13.1% to 53.9% ± 19.4% at 6 Hz of stimulation in the gastrocnemius. There were no significant improvements in walking function. Conclusions: Treadmill training can improve muscle oxidative capacity and endurance in people with MS who have moderate-to-severe levels of disability.