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To test the hypothesis that long-term immunological response may be different after accustomed concentric and unaccustomed eccentric exercise in endurance-trained men.Fourteen highly endurance-trained male runners performed two bouts of high-intensity exercise with at least 2-wk intervals between bouts. Concentric exercise consisted of a 60-min level run with a targeted heart rate of 80% V˙O2peak. Eccentric exercise was conducted lying on a specially designed exercise rack, eliciting eccentric action of the musculus quadriceps femoris. Blood samples were taken before and 1, 6, 24, 72, and 144 h after exercise to determine creatine kinase (CK), C-reactive protein (CRP), and interleukin-6 (IL-6). Lymphocyte subset distribution was assessed using flow cytometry.We found a significant (P < 0.05) increase of CD4+ (eccentric: 17%; concentric: 20%), CD3+/CD4+ (16 vs 19%), CD25+ (45 vs 29%), CD25+/CD4+ (27 vs 50%), HLA-DR+ (20 vs 15%), HLA-DR+/CD4+ (16 vs 67%), and CD19+/CD45+ (52 vs 103%) positive lymphocytes 1 h after both exercise bouts. However, eccentric exercise resulted in a significantly higher and longer (6 h) increase of CD25+/CD4+ and HLA-DR+/CD8+ lymphocytes and a peak increase of CK at 72 h. IL-6 and CRP increased only after concentric exercise within the first 24 h. Both exercises resulted in a decrease of monocyte activation (LFA-1: CD18+/CD11a+) after 6 h, with an increase for the eccentric exercise part after 24 h (P < 0.05).Accustomed concentric exercise mainly induced an acute-phase response, with increased CRP, IL-6, and activation of CD4+ lymphocyte subsets. Unaccustomed eccentric exercise provided a delayed increase in CK and activation of monocytes and CD4+ and CD8+ subsets. Therefore, the immunological reaction depends not only on the type of contraction but also on the adaptation to the exercise.