This study examined adaptation to isometric exercise with regard to changes in serum creatine kinase (CK) activity and muscle soreness. Forty-five college-age males were placed into six groups, each performing two bouts of strenuous isometric exercise of the knee extensors. In experiment 1 (N = 27), after performing the first bout of exercise, groups A, B, and C performed the second bout 3, 6, and 9 wk later, respectively. In experiment 2 (N = 18), groups D, E, and F performed the second exercise bout 1, 2, and 3 wk after the first bout, respectively. In experiment 3, group D performed two additional exercise bouts; thus, this group performed a total of four bouts spaced 1 wk apart. Muscle soreness and CK were assessed prior to and 6, 18, and 24 (or 42) h following each exercise. In experiment 1, no significant difference in soreness or serum CK was found between bouts 1 and 2. In experiment 2, a significant decrease in the CK and soreness responses was found on bout 2 compared with bout 1 (P less than 0.05). In experiment 3, serum CK and soreness responses were highest following bout 1 while bouts 2, 3, and 4 were not significantly different from one another. Performance of this isometric exercise results in an adaptation that lasts approximately 3 wk, with the greatest adaptation occurring after one bout.