BACKGROUND: Ondansetron is a 5-HT3 receptor antagonist with potent antiemetic, analgesic, and antiphlogistic effects. Recent evidence suggests that the co-existence of 5-HT3 receptors in various cell types is involved in inflammation. However, the effects that 5-HT3 antagonists produce in haemorrhagic shock and resuscitation remain unknown. In this study, we hypothesized that ondansetron administration in male rats, after haemorrhagic shock, decreases cytokine production and protects against hepatic injury through a p38 mitogen-activated protein kinase (MAPK) pathway. METHODS: Male Sprague-Dawley rats underwent haemorrhagic shock (mean arterial blood pressure 40mmHg for 90min), followed by resuscitation. Various doses of ondansetron (0.1, 0.3, 1, 3mgkg(-1)) or a single dose of ondansetron (1mgkg(-1)) with or without a p38 MAPK inhibitor (SB-203580, 2mgkg(-1)) or vehicle were administered intravenously during resuscitation. Plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations and various liver proinflammatory parameters were measured at 24h after resuscitation. RESULTS: Results show that haemorrhagic shock increases plasma AST and ALT concentrations, hepatic myeloperoxidase activity, cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-3, intercellular adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) levels. These parameters were significantly improved in the ondansetron-treated rats subjected to haemorrhagic shock. Ondansetron treatment restored phos-p38 MAPK expression as compared with vehicle-treated haemorrhaged rats. Coadministration of SB-203580 prevented the beneficial effects of ondansetron on postresuscitation proinflammatory responses and hepatic injury. CONCLUSION: Ondansetron attenuates hepatic injury following haemorrhagic shock, which is, at least in part, to be due to its anti-inflammatory effect via p38 MAPK signal pathway.