Objective: To test the hypothesis that lower body progressive resistance training (PRT) leads to an increase of the muscle fiber cross-sectional area (CSA) and a shift in the proportion of fiber types in patients with multiple sclerosis (MS). Methods: The present study was a two-arm, randomized controlled trial (RCT). Thirty-eight MS patients (Expanded Disability Status Scale (EDSS) 3—5.5) were randomized to a PRT group (Exercise, n = 19) or a control group (Control, n = 19). The Exercise group performed a biweekly 12-week lower body PRT program [five exercises progressing from 15RM (Repetition Maximum) towards 8RM], whereas the Control group maintained their usual daily activity level during the trial period. Muscle biopsies from vastus lateralis were taken before (pre) and after the trial (post). Thigh volume (TV) was estimated from anthropometric measurements. Isokinetic muscle strength of the knee extensors (KE) and flexors (KF) were evaluated at slow (90^°/s) and fast (180^°/s) angular velocities. Results: In the Exercise group the mean CSA of all muscle fibers (7.9 ± 15.4% vs. -3.5 ± 9.0%, p = 0.03) and of type II muscle fibers (14.0 ± 19.4% vs. -2.6 ± 15.5%, p = 0.02) increased in comparison with the Control group. No changes occurred in the proportion of fiber types in the Exercise group. Neither was there any change in total TV. Isokinetic strength at KE180, KF90 and KF180 improved significantly after PRT when compared with the control group (10.2—21.3%, p ≤ 0.02). Conclusions: We conclude that progressive resistance training induces a compensatory increase of muscle fiber size in patients with the central nervous system disorder, multiple sclerosis.