BACKGROUND Bed rest studies have shown that high load (HL) resistance training can mitigate the loss of muscle size and strength during musculoskeletal unloading; however, not all individuals are able to perform HL resistance exercise. Blood flow restricted (BFR) resistance exercise may be a novel way to prevent maladaptation to unloading without requiring HL exercise equipment. This study evaluated the muscular training adaptations to HL and BFR resistance training during unilateral lower limb suspension (ULLS), a human limb unloading model. ULLS allows for evaluation of exercise training in both weight-bearing and nonweight-bearing legs within the same individual. METHODS There were 13 participants who completed 25 d of ULLS and were counterbalanced to: 1) HL, N = 6; or 2) BFR, N = 7, training groups. During ULLS, HL and BFR performed unilateral leg press and heel raise exercise (3 d/wk). RESULTS In weight-bearing legs, both HL and BFR increased knee extensor muscle cross-sectional area (CSA) and strength. In nonweight-bearing legs, knee extensor CSA and strength increased only in HL and decreased with BFR. CONCLUSIONS HL and BFR resistance exercise were both effective exercise programs for the weight-bearing leg. However, BFR exercise was not as effective as HL resistance exercise in the nonweight-bearing leg. These data show that exercise that improved muscle CSA and strength in ambulatory weight-bearing conditions was not sufficient to maintain muscle function during unloading. For the preservation of muscle CSA and strength, BFR exercise should be considered an adjunct but not a primary exercise countermeasure for future space missions. Hackney KJ, Downs ME, Ploutz-Snyder L. Blood flow restricted exercise compared to high load resistance exercise during unloading. Aerosp Med Hum Perform. 2016; 87(8):688-696.