Previous reports have shown that arginine (Arg) enhances phagocytic activity of macrophages and is required for macrophage-mediated toxicity toward tumor cells. Few studies have addressed the importance of Arg supplementation on macrophage and neutrophil function after infection and sepsis. This study examined the effect of Arg-supplemented diets before and Arg-enriched total parenteral nutrition (TPN) after sepsis or both on the phagocytic activity of peritoneal macrophages and blood polymorphonuclear cells in rats with gut-derived sepsis. Male Wistar rats were assigned to 4 groups. Groups 1 and 2 were fed a semipurified diet, while groups 3 and 4 had part of the casein replaced with 2% of total calories as Arg. After the experimental diets were administered for 10 days, sepsis was induced by cecal ligation and puncture (CLP); at the same time, an internal jugular vein was cannulated. All rats were maintained on TPN for 3 days. Groups 1 and 3 were infused with conventional TPN, while groups 2 and 4 were supplemented with Arg, replacing 10% of total amino acids in the TPN solution. Survival rates were recorded for 3 days after CLP, and all surviving rats were killed 3 days after CLP to examine their immune responses. Aerobic and anaerobic bacteria colony counts in peritoneal lavage fluid were significantly reduced, and the phagocytic activity of peritoneal macrophages was enhanced in groups 3 and 4 but not in the other 2 groups. There were no significant differences in the phagocytic activities of blood polymorphonuclear cells and survival rates among the 4 groups. Enteral Arg supplementation before sepsis significantly enhanced peritoneal macrophage phagocytic activity and reduced total bacterial counts in peritoneal lavage fluid. Arg administered before and after CLP seemed to have a synergistic effect on enhancing phagocytic activity and on bacterial clearance. However, IV Arg administration after CLP had no favorable effects on phagocytic activity or survival rates in rats with gut-derived sepsis.