Coelho, DB, Pimenta, EM, Rosse, IC, Veneroso, C, Pussieldi, GDA, Becker, LK, De Oliveira, EC, Carvalho, MRS, and Silami-Garcia, E. Alpha-actinin-3 R577X polymorphism influences muscle damage and hormonal responses after a soccer game. J Strength Cond Res 33(10): 2655-2664, 2019-The purpose of this study was to evaluate indicators of muscle damage and hormonal responses after soccer matches and its relation to alpha-actinin-3 (ACTN3) gene expression (XX vs. RR/RX), considering that the R allele produces alpha-actinin-3 and provides greater muscle strength and power. Thirty players (10 XX and 20 RR/RX) younger than 16 years were evaluated in this study. Blood samples were collected immediately before, after, 2, and 4 hours after the games to assess muscle damage (creatine kinase [CK] and alpha-actin) and hormonal responses (interleukin-6 [IL-6], cortisol, and testosterone). Postgame CK was higher as compared to the pregame values in both groups and it was also higher in the RR/RX (p < 0.05) than in the XX. The concentrations of alpha-actin and IL-6 were similar for both groups and did not change over time. Testosterone was increased after the game only in the RR/RX group (p < 0.05). Cortisol concentrations in group RR/RX were higher immediately after the game than before the game, and 2 and 4 hours after the game the concentration decreased (p < 0.05). The RR and RX individuals presented higher markers of muscle microtrauma and hormonal stress, probably because they performed more speed and power actions during the game, which is a self-regulated activity. From the different responses presented by RR/RX and XX genotypes, we conclude that the genotypic profile should be taken into account when planning training workloads and recovery of athletes.