Suggested mechanisms for the systemic, circulating cytokinemia observed during heavy physical exertion include inflammation and energy demand. We compared cytokine levels and examined the underlying physiological mechanisms between a long-distance triathlon and a 100-km run, two endurance races of similar duration but characterized by differences in muscle strain. Blood samples were collected from 12 triathletes (34.8 +/- 1.4 yr) and 11 runners (42.4 +/- 2.2 yr) the day before and at the end of races (T1, R1), and 24 h and 7 days post-race (R2, R3). At R1, significant race-related differences were observed, with greater increases in plasma levels of interleukins (IL)-6, IL-1ra, and IL-10 in the triathletes than in the runners, while levels of the chemokine IL-8 increased solely in the runners (P < 0.05, P < 0.05, P < 0.01, and P < 0.001, respectively). At R1, free fatty acid (FFA) levels were 119% higher in the triathletes than in the runners, who were the most liable to muscle damage in view of increased levels of the muscle-specific enzyme, creatine kinase (CK), loss of muscle flexibility and decreased physical performance. At R1, levels of heat shock protein (HSP)72 increased in the two groups but were 173% higher in the runners. For the two groups, all parameters had returned to pre-race levels by seven days post-race. Positive correlations were noted between IL-6 and FFA in the triathletes and between IL-8 and CK and HSP72 in the runners. The differences between cytokine responses after a long distance triathlon and a 100-km run suggested that IL-6 and IL-8 could be employed as respective markers of the intensity of the muscular activity required for substrate availability and vascular inflammation.