The optimal volume of resistance exercise to prescribe for trained individuals is unclear. The purpose of this study was to randomly assign resistance trained individuals to 6-weeks of squat exercise, prescribed at 80% of a 1 repetition-maximum (1-RM), using either one, four, or eight sets of repetitions to failure performed twice per week. Participants then performed the same peaking program for 4-weeks. Squat 1-RM, quadriceps muscle activation, and contractile rate of force development (RFD) were measured before, during, and after the training program. 32 resistance-trained male participants completed the 10-week program. Squat 1-RM was significantly increased for all groups after 6 and 10-weeks of training (P < 0.05). The 8-set group was significantly stronger than the 1-set group after 3-weeks of training (7.9% difference, P < 0.05), and remained stronger after 6 and 10-weeks of training (P < 0.05). Peak muscle activation did not change during the study. Early (30, 50 ms) and peak RFD was significantly decreased for all groups after 6 and 10-weeks of training (P < 0.05). Peak isometric force output did not change for any group. The results of this study support resistance exercise prescription in excess of 4-sets (i.e. 8-sets) for faster and greater strength gains as compared to 1-set training. Common neuromuscular changes are attributed to high intensity squats (80% 1-RM) combined with a repetition to failure prescription. This prescription may not be useful for sports application owing to decreased early and peak RFD. Individual responsiveness to 1-set of training should be evaluated in the first 3-weeks of training.