Perfluorochemicals (PFC) are chemical substances that have a high solubility for oxygen. This study investigated the effect of peritoneal lavage with oxygenated PFC (O2-PFC) against hemorrhagic shock and resuscitation (HS/R). Male Sprague-Dawley rats were anesthetized and bled to a mean arterial pressure (MAP) of 30 to 35 mmHg for 120 min. The animals then were resuscitated over 20 min with an infusion of shed blood. Peritoneal lavage was performed by inflow and outflow of the PFC solution at 80 mL/h during the shock-resuscitation period. Rats were divided into four groups. Group I, HS without peritoneal lavage; Group II, HS with nitrogenated PFC (N2-PFC) lavage; Group III, HS with O2-PFC lavage; and Group IV, sham-operated rats. Seven of seven (100%) rats in Group IV and six of seven (85.7%) rats in Group III survived for 48 h, and one of seven (14.3%) rats in Group I and zero of seven rats in Group II survived (P < 0.01). In Group III rats, metabolic acidosis (assessed by blood gas analysis) and depression of intestinal blood flow (assessed by laser Doppler flowmetry) during HS were markedly ameliorated in comparison with those in Group I or Group II rats. The elevation of plasma TNF-alpha and IL-6 after HS/R were also attenuated in Group III. Histological study showed that O2-PFC lavage significantly decreased the degree of intestinal mucosal damage. We conclude that treatment with O2-PFC lavage ameliorated HS/R-induced metabolic acidosis and intestinal damage, which was associated with better mortality, possibly by preserving microvascular perfusion and maintaining oxygen metabolism.