To examine the effects of different rest intervals between sets on serum creatine kinase (CK) and lactate dehydrogenase (LDH) activity, 10 men (age = 25.6 ± 2.2 years, height = 173.1 ± 7.1 cm, and body mass = 75.9 ± 10.0 kg) participated in a randomized within-subject design that involved 4 resistance exercise sessions. Each session consisted of 4 sets of 10 repetitions with 10 repetition maximum loads for the chest press, pullover, biceps curl, triceps extension, leg extension, and prone leg curl. The sessions differed only in the length of the rest interval between sets and exercises, specifically: 60, 90, 120, 180 seconds. Serum CK and LDH were significantly (p < 0.05) elevated 24-72 hours after each session, with no significant differences between rest intervals (p = 0.94 and p = 0.99, respectively). The mechanical stress imposed by the 4 resistance exercise sessions invoked similar damage to the muscle fibers independent of the rest interval between sets. These data indicate that the accumulated volume of work is the primary determinant of muscle damage in trained subjects who are accustomed to resistance exercise with short rest intervals.