OBJECTIVE This study examined sex differences in strength loss, muscle soreness, and serum creatine kinase (CK) and myoglobin (Mb) after high-intensity eccentric exercise of the elbow flexors in a large group of men and women. METHODS One hundred participants (58 women, 42 men) performed 50 maximal eccentric contractions of the elbow flexor muscles of their nondominant arm. Maximum isometric voluntary contraction (MVC) was recorded at baseline, immediately after exercise, and at 0.5 (12-14 h), 3, 4, 7, and 10 d after exercise. Blood samples for serum CK activity and Mb were taken at baseline and at 4, 7, and 10 d after exercise. Soreness was evaluated at baseline and at 0.5, 3, 4, 7, and 10 d after exercise. RESULTS Women experienced significantly greater relative strength loss immediately after exercise (-57.8% +/- 19.1) than men (-50.4% +/- 16.9%) (independent t-test; P < or = 0.05), and a greater percentage of women experienced more than 70% strength loss immediately after exercise compared with men (34.4% of women; 7.1% of men). Men exhibited a larger CK response compared with women (ANCOVA; P < or = 0.05), partly because there were more men who were high responders. There were no significant differences between the sexes for serum Mb or soreness measures. Generally, stronger relationships among CK, soreness, and strength-loss measures were found in men compared with women (r = 0.55-0.59 for men; r = 0.12-0.49 for women). CONCLUSIONS In response to eccentric exercise, women experienced greater immediate strength loss than men and were more likely to be high responders for immediate strength loss; men experienced greater serum CK activity than women and were more likely to be high responders for increased serum CK. Although the explanation for high responders to eccentric exercise remains unknown, we have shown that there are sex-specific differences in CK and strength-loss response after eccentric exercise.