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Unaccustomed exercise may cause muscle breakdown with marked increase in serum creatine kinase (CK) activity. The skeletal muscle renin-angiotensin system (RAS) plays an important role in exercise metabolism and tissue injury. A functional insertion (I) / deletion (D) polymorphism in the angiotensin-I converting enzyme (ACE) gene (rs4646994) has been associated with ACE activity. We hypothesized that ACE ID genotype may contribute to the wide variability in individuals ' CK response to a given exercise. Young individuals performed maximal eccentric contractions of the elbow flexor muscles. Pre- and post-exercise CK activity was determined. ACE genotype was significantly associated with post-exercise CK increase and peak CK activity. Individuals harboring one or more of the I allele had a greater increase and higher peak CK values than individuals with the DD genotype. This response was dose-dependent (mean ± S.E.M. U/L: II, 8882 ± 2362; ID, 4454 ± 1105; DD, 2937 ± 753, ANOVA, P = 0.02; P = 0.009 for linear trend). Multivariate stepwise regression analysis, which included age, sex, BMI, and genotype subtypes revealed that ACE genotype was the most powerful independent determinant of peak CK activity (adjusted odds ratio 1.3, 95 % confidence interval 1.03 – 1.64, P = 0.02). I