The purpose of this study was to compare squat strength gains and volume components when resting 2 minutes vs. 4 minutes between sets over multiple mesocycles. After the first squat 1 repetition maximum, 15 trained men were matched and randomly assigned to either a 2-minute (n = 7) or a 4-minute (n = 8) rest interval group. Each group performed the same training program, with the only difference being the length of the rest interval between sets. Subjects performed two squat workouts per week; one was labeled as Heavy and the other was labeled as Light. The squat workouts varied in the intensity, number of sets, and repetitions performed per set in a nonlinear periodized manner throughout each mesocycle. Differences in strength gains and volume components (the load utilized per set, the repetitions performed per set, the intensity per set, and the volume performed per workout) were compared between groups. Both groups demonstrated large strength gains; however, these differences were not significant between groups (P = 0.47). During all mesocycles, the 4-minute group demonstrated significantly higher total volumes for the Heavy workouts (P < 0.05). The findings of the present study indicate that large squat strength gains can be achieved with a minimum of 2 minutes' rest between sets, and little additional gains are derived from resting 4 minutes between sets. Therefore, athletes attempting to achieve specific volume goals may need longer rest intervals initially but may later adapt so that shorter rest intervals can be utilized without excessive fatigue, leaving additional time to focus on other conditioning priorities.