The purpose of this study was to compare the effects of single- and multiple-set strength training on hypertrophy and strength gains in untrained men. Twenty-one young men were randomly assigned to either the 3L-1UB group (trained 3 sets in leg exercises and 1 set in upper-body exercises; n = 11), or the 1L-3UB (trained 1 set in leg exercises and 3 sets in upper-body exercises; n = 10). Subjects trained 3 days per week for 11 weeks and each workout consisted of 3 leg exercises and 5 upper-body exercises. Training intensity varied between 10 repetition maximum (RM) and 7RM. Strength (1RM) was tested in all leg and upper-body exercises and in 2 isokinetic tests before training, and after 3, 6, 9, and 11 weeks of training. Cross sectional area (CSA) of thigh muscles and the trapezius muscle and body composition measures were performed before training, and after 5 and 11 weeks of training. The increase in 1RM from week 0 to 11 in the lower-body exercises was significantly higher in the 3L-1UB group than in the 1L-3UB group (41 vs. 21%; p < 0.001), while no difference existed between groups in upper-body exercises. Peak torque in maximal isokinetic knee-extension and thigh CSA increased more in the 3L-1UB group than in the 1L-3UB group (16 vs. 8%; p = 0.03 and 11 vs. 7%; p = 0.01, respectively), while there was no significant difference between groups in upper trapezius muscle CSA. The results demonstrate that 3-set strength training is superior to 1-set strength training with regard to strength and muscle mass gains in the leg muscles, while no difference exists between 1- and 3-set training in upper-body muscles in untrained men.