Del Coso, J, Salinero, JJ, Lara, B, Gallo-Salazar, C, Areces, F, Herrero, D, and Puente, C. Polygenic profile and exercise-induced muscle damage by a competitive half-ironman. J Strength Cond Res XX(X): 000–000, 2017—To date, it is still unknown why some individuals develop higher levels of muscle damage than other individuals, despite participating in exercise with comparable levels of physical intensity. The aim of this investigation was to analyze 7 single-nucleotide polymorphisms (SNPs) that are candidates to explain individual variations in the level of muscle damage attained during a half-ironman competition. Using the model of Williams and Folland (2, 1, and 0 points for optimal, intermediate, and suboptimal genotype), we determined the total genotype score from the accumulated combination of 7 SNPs (ACE = 287bp Ins/Del; ACTN3 = p.R577X; creatine kinase, muscle type = NcoI; insulin-like growth factor 2 = C13790G; interleukin-6 = 174G>C; myosin light chain kinase = C37885A; and tumor necrosis factor–α = 308G>A) in 22 experienced triathletes. Before and after the race, a sample of venous blood was obtained to measure serum markers of muscle damage. Two groups of triathletes were established according to their postcompetition serum CK concentration: low CK responders (n = 10; 377 ± 86 U·L−1) vs. high CK responders (n = 12; 709 ± 136 U·L−1). At the end of the race, low CK responders had lower serum myoglobin concentrations (384 ± 243 vs. 597 ± 293 ng·ml−1, p = 0.04). Although the groups were similar in age, anthropometric characteristics, and training habits, total genotype score was higher in low CK responders than in high CK responders (7.7 ± 1.1 vs. 5.5 ± 1.1 point, p < 0.01). A favorable polygenic profile can contribute to reducing the level of muscle damage developed during endurance exercise.