The purpose of this study was to determine the effect of cryotherapy on the inflammatory response to muscle-damaging exercise using a randomized trial. Twenty recreationally active males completed a 40-min run at a -10 % grade to induce muscle damage. Ten of the subjects were immersed in a 5 °C ice bath for 20 min and the other ten served as controls. Knee extensor peak torque, soreness rating, and thigh circumference were obtained pre- and post-run, and 1, 6, 24, 48, and 72 h post-run. Blood samples were obtained pre- and post-run, and 1, 6 and 24 h post-run for assay of plasma chemokine ligand 2 (CCL2). Peak torque decreased from 270 ± 57 Nm at baseline to 253 ± 65 Nm post-run and increased to 295 ± 68 Nm by 72 h post-run with no differences between groups (p = 0.491). Soreness rating increased from 3.6 ± 6.0 mm out of 100 mm at baseline to 47.4 ± 28.2 mm post-run and remained elevated at all time points with no differences between groups (p = 0.696). CCL2 concentrations increased from 116 ± 31 pg mL(-1) at baseline to 293 ± 109 pg mL(-1) at 6 h post-run (control) and from 100 ± 27 pg mL(-1) at baseline to 208 ± 71 pg mL(-1) at 6 h post-run (cryotherapy). The difference between groups was not significant (p = 0.116), but there was a trend for lower CCL2 in the cryotherapy group at 6 h (p = 0.102), though this measure was highly variable. In conclusion, 20 min of cryotherapy was ineffective in attenuating the strength decrement and soreness seen after muscle-damaging exercise, but may have mitigated the rise in plasma CCL2 concentration. These results do not support the use of cryotherapy during recovery.