The study's purpose was to compare the response of performing 1, 3, and 5 sets on measures of performance and muscle hypertrophy. Forty-eight men, with no weight training experience, were randomly assigned to one of the 3 training groups, 1 SET, 3 SETS, 5 SETS, or control group. All training groups performed 3 resistance training sessions per week for 6 months. The 5 repetition maximum (RM) for all training groups increased in the bench press (BP), front lat pull down (LPD), shoulder press (SP), and leg press (LP) (p ≤ 0.05), with the 5 RM increases in the BP and LPD being significantly greater for 5 SETS compared with the other training groups (p ≤ 0.05). Bench press 20 RM in the 3-SET and 5-SET groups significantly increased with the increase being significantly greater than the 1-SET group and the 5-SET group increase being significantly greater than the 3-SET group (p ≤ 0.05). LP 20 RM increased in all training groups (p ≤ 0.05), with the 5-SETS group showing a significantly greater increase than the 1-SET group (p ≤ 0.05). The 3-SET and 5-SET groups significantly increased elbow flexor muscle thickness (MT) with the 5-SET increase being significantly greater than the other 2 training groups (p ≤ 0.05). The 5-SET group significantly increased elbow extensor MT with the increase being significantly greater than the other training groups (p ≤ 0.05). All training groups decreased percent body fat, increased fat-free mass, and vertical jump ability (p ≤ 0.05), with no differences between groups. The results demonstrate a dose-response for the number of sets per exercise and a superiority of multiple sets compared with a single set per exercise for strength gains, muscle endurance, and upper arm muscle hypertrophy.