Purpose Resistance training (RT) can improve functional outcomes among people with multiple sclerosis (PwMS) but is underutilized due to the use of heavy training loads. Low-load resistance training with blood-flow restriction (RT + BFR) may provide an alternative. Therefore, the purpose of this study was to evaluate the effects of 12 weeks of low-load RT + BFR and heavy-load RT on functional outcomes among PwMS. Methods Seventeen PwMS (EDSS 0 to 6.5) completed 12 weeks (2x/week) of heavy-load (65% of one-repetition maximum [1RM]; n = 9) RT or low-load (30% of 1RM; n = 8) RT + BFR. Functional outcomes including gait speed (self-selected and fast 10-meter Walk Test [10mWT]), walking endurance (6 Minute Walk Test [6MWT]), leg strength/transfers (Five Times Sit to Stand Test [5xSTS], 30 Second Sit to Stand Test [30CST]), and fatigue (Modified Fatigue Impact Scale [MFIS]) were assessed every four weeks. Results Improvements in 10mWT (fast) occurred earlier for low-load RT + BFR (1.31 ± 0.24 to 1.79 ± 0.53 m/s from week 0 to 8; p = 0.005) than heavy-load RT (1.19 ± 0.31 to 1.63 ± 0.58 m/s from week 4 to 12; p = 0.005). MFIS was lower for low-load RT + BFR (16.25 ± 15.59 au) compared to heavy-load RT (32 ± 13.63 au) after 4 weeks (p = 0.042). 6MWT only improved in heavy-load RT from baseline to week 12 (309.1 ± 97.5 to 390.5 ± 100.4 m; p = 0.001), although baseline walking distance was higher in the low-load RT + BFR group (429.3 ± 42.1 m; p = 0.006). Improvements in 5xSTS and 30CST were similar for both groups. Conclusions Low-load RT + BFR and heavy-load RT elicited comparable improvements among indices of strength, endurance, and walking speed with greater improvements in fatigue from low-load RT + BFR in PwMS. Thus, low-load RT + BFR may be a valuable modality to improve functional outcomes among PwMS in situations where heavy-load RT is intolerable. © 2025 American College of Sports Medicine.