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ABSTRACT Costilla, M, Casals, C, Marín-Galindo, A, Sánchez-Sixto, A, Muñoz-López, A, Sañudo, B, Corral-Pérez, J, and Ponce-González, JG. Changes in muscle deoxygenation during squat exercise after 6-week resistance training with different percentages of velocity loss. J Strength Cond Res XX(X): 000-000, 2022-The present study compared, for the first time, the effects of 6 weeks of 20% (20VL) vs. 40% (40VL) velocity loss (VL) resistance training (RT) programs on muscle oxygen dynamics during the squat exercise. Twenty-three young men (21.4 ± 2.4 years) were randomly allocated into the 20VL group (n = 8), 40VL group (n = 7), or control group (CG; n = 8). The RT program consisted of 3 sets of Smith machine back squat exercise at 20VL or 40VL with a 3-minute rest between sets, twice per week for 6 weeks. Tissue oxygenation index (TOI) was measured using near-infrared spectroscopy in the vastus medialis and vastus lateralis during a squat test (8-repetition 1 m·s-1 load test), and the maximum (maxTOI) and minimum (minTOI) TOIs were measured during a 3-min recovery period. After the 6-week RT program, TOI increased significantly at the beginning of the test in both muscles (during the first 4 repetitions in the vastus lateralis and 5 repetitions in the vastus medialis) in the 20VL group (p < 0.05), with nonsignificant changes in the 40VL group and CG. The maxTOI was significantly increased in the vastus medialis (+3.76%) and vastus lateralis (+3.97%) after the training only in the 20VL group (p < 0.05). The minTOI in the vastus medialis reached during the test remained unchanged postintervention for both training groups, with the CG showing significantly higher values compared with the 20VL group (+14.1%; p < 0.05). In conclusion, depending on the VL reached during a squat RT program, different changes in muscle oxygen dynamics can be expected. Training at 20% of VL improves metabolic efficiency and the reoxygenation peak after the set.