Based on clinical data revealing a promising immunomodulatory effect of clarithromycin in sepsis due to ventilator-associated pneumonia, the efficacy of clarithromycin in experimental peritonitis and sepsis was assessed with particular emphasis on immune function. Cecal puncture and ligation was performed in rabbits assigned to the following groups: Group A, controls (n=12); Group B, intravenous clarithromycin treatment (n=15); Group C, piperacillin/tazobactam (TZP) treatment (n=10); Group D, clarithromycin+TZP combination treatment (n=12). Blood was sampled at serial time intervals and peripheral blood mononuclear cells (PBMCs) were isolated. Apoptosis of lymphocytes and monocytes was measured by flow cytometric analysis. PBMCs were stimulated with lipopolysaccharide (LPS) and Pam3Cys for the release of tumour necrosis factor-alpha (TNFα). Tissue bacterial growth was quantitatively measured after death or sacrifice. Survival in Group D after 10 days was prolonged compared with the other groups. Early apoptosis of lymphocytes in Group B was lower compared with Group D at 2h and compared with Group C at 4h. Early apoptosis of monocytes in Group B was lower compared with Group C at 24h. Following stimulation of PBMCs with LPS, release of TNFα was decreased in Group B compared with Groups A and D at 2h. Bacterial growth in tissues of Groups C and D was decreased compared with Group A. It is concluded that clarithromycin modulates the function of the immune response in experimental peritonitis by decreasing the rate of early apoptosis of lymphocytes and monocytes and by decreasing the ex vivo release of TNFα by blood monocytes.