Context: Compression socks have become increasingly popular with athletes due to perceived enhancement of exercise performance and recovery. However, research examining the efficacy of compression socks to reduce exercise-associated muscle damage has been equivocal, with few direct measurements of markers of muscle damage. Objective: To examine the influence of compression socks worn during a marathon on creatine kinase (CK) levels. Design: A randomized controlled trial. Setting: 2013 Hartford Marathon, Hartford, CT. Participants: Adults (n = 20) randomized to control (CONTROL; n = 10) or compression sock (SOCK; n = 10) groups. Main Outcome Measures: Blood samples were collected 24 hours before, immediately after, and 24 hours following the marathon for the analysis of CK, a marker of muscle damage. Results: Baseline CK levels did not differ between CONTROL (89.3 [41.2] U/L) and SOCK (100.0 [56.2] U/L) (P = .63). Immediately following the marathon (≤1 h), CK increased 273% from baseline (P < .001 for time), with no difference in exercise-induced changes in CK from baseline between CONTROL (+293.9 [278.2] U/L) and SOCK (+233.1 [225.3] U/L; P = .60 for time × group). The day following the marathon (≤24 h), CK further increased 1094% from baseline (P < .001 for time), with no difference in changes in CK from baseline between CONTROL (+ 1191.9 [1194.8] U/L) and SOCK (+889.1 [760.2] U/L; P = .53 for time × group). These similar trends persisted despite controlling for potential covariates such as age, body mass index, and race finishing time (Ps > .29). Conclusions: Compression socks worn during a marathon do not appear to mitigate objectively measured markers of muscle damage immediately following and 24 hours after a marathon.