Lasevicius, T, Schoenfeld, BJ, Silva-Batista, C, Barros, TdS, Aihara, AY, Brendon, H, Longo, AR, Tricoli, V, Peres, BdA, and Teixeira, EL. Muscle failure promotes greater muscle hypertrophy in low-load but not in high-load resistance training. J Strength Cond Res 36(2): 346–351, 2022—The purpose of this study was to investigate the effects of an 8-week resistance training program at low and high loads performed with and without achieving muscle failure on muscle strength and hypertrophy. Twenty-five untrained men participated in the 8-week study. Each lower limb was allocated to 1 of 4 unilateral knee extension protocols: repetitions to failure with low load (LL-RF; ∼34.4 repetitions); repetitions to failure with high load (HL-RF; ∼12.4 repetitions); repetitions not to failure with low load (LL-RNF; ∼19.6 repetitions); and repetitions not to failure with high load (HL-RNF; ∼6.7 repetitions). All conditions performed 3 sets with total training volume equated between conditions. The HL-RF and HL-RNF protocols used a load corresponding to 80% 1 repetition maximum (RM), while LL-RF and LL-RNF trained at 30% 1RM. Muscle strength (1RM) and quadriceps cross-sectional area (CSA) were assessed before and after intervention. Results showed that 1RM changes were significantly higher for HL-RF (33.8%, effect size [ES]: 1.24) and HL-RNF (33.4%, ES: 1.25) in the post-test when compared with the LL-RF and LL-RNF protocols (17.7%, ES: 0.82 and 15.8%, ES: 0.89, respectively). Quadriceps CSA increased significantly for HL-RF (8.1%, ES: 0.57), HL-RNF (7.7%, ES: 0.60), and LL-RF (7.8%, ES: 0.45), whereas no significant changes were observed in the LL-RNF (2.8%, ES: 0.15). We conclude that when training with low loads, training with a high level of effort seems to have greater importance than total training volume in the accretion of muscle mass, whereas for high load training, muscle failure does not promote any additional benefits. Consistent with previous research, muscle strength gains are superior when using heavier loads.