PURPOSE To determine whether or not creatine phosphokinase (CPK) release during ultramarathon race competition is related to changes in plasma cytokines. METHODS Subjects included 60 ultramarathoners (mean±SE, age 45.3±1.1 yr) who had been training for 13.9±1.3 yr, and finished the 160-km race in under 30 h (26.3±0.4 h). Subjects provided training information through questionnaires, and recorded perceptions of muscle soreness during the week following the race using a 10-point Likert scale (DOMS) (1=no soreness, 4=slight soreness, 7=sore, and 10=unbearably sore). Blood samples were collected the morning prior to and immediately following the 2004 160-km Western States Endurance Run. Complete blood counts and 7 plasma cytokines and chemokines were measured (IL-6, IL-10, IL-8, IL-1ra, granulocyte colony-stimulating factor or G-CSF, monocyte chemotactic protein 1 or MCP-1, and macrophage inflammatory protein 1 beta or MIP-1β). Changes in these plasma cytokines/chemokines were correlated with changes in CPK and the DOMS scale. RESULTS Significant increases were measured for all 7 cytokines/chemokines, with the greatest fold increase seen for IL-6 (125×), and then IL-10 (24×), G-CSF (12×), IL-1ra (7×), IL-8 (4×), MCP-1 (3×), and MIP-1β(1.2×). CPK increased from 159±21 to 17,833±2,883 U/L, and change in CPK was significantly correlated with changes in IL-6 (r=0.68, P<0.001), G-CSF (r=0.67, P<0.001), IL-10 (r=0.53, P<0.001), IL-1ra (r=0.50, P<0.001), and MCP-1 (r=0.49, P<0.001), but not IL-8 or MIP-1β. DOMS averaged 7. 1±0.3 the day after the race, and 5.0±0.3, 2.5±0.2, and 1.6±0.1 3-d, 5-d, and 7-d post-race, respectively, and each was significantly correlated with CPK (r=0.40 to 0.63, P<0.001) and changes in IL-6, G-CSF, IL-10, and MCP-1 (r=0.28 to 0.77, P<0.05). Use of NSAIDS during the race was reported by 72% of the athletes. A comparison of NSAID users and nonusers showed no differences in CPK or DOMS, but did reveal significantly greater increases in IL-6, IL-8, G-CSF, MCP-1, and MIP-1β in the NSAID users (P<0.05). Self-selected use of antioxidant supplements either in the months before (70%) or during the race (18%) had no effect on CPK, DOMS, or changes in cytokines/chemokines. CONCLUSION Muscle damage in athletes competing in a 160-km race was significantly correlated with post-race DOMS and increases in 5 of 7 cytokines/chemokines. Ultramarathoners using NSAIDS did not experience a reduction in muscle damage or DOMS, but did have higher post-race levels in 5 of 7 cytokines/chemokines. Supported by the 160-km Western States Endurance Run Medical Board, and the Gatorade Sports Science Institute.