Despite antibiotics, infection remains a significant problem in surgical patients. The reasons are multiple, and include acquired immunologic deficiencies that are seen in malnutrition, sepsis, trauma, and burns. Two immunomodulators, thymopentin (TP-5) and CP-46,665, have been shown to improve survival in infectious animal models of such deficiencies. We investigated the mechanism of action in guinea pigs subjected to a burn of 30% of the total body surface area. These animals received 0.3 mg/kg of thymopentin, 0.3 mg/kg of CP-46,665, or saline solution. Neutrophils, macrophages, and serum samples were obtained from the animals and tested for their ability to phagocytose and kill Pseudomonas aeruginosa. The serum was tested for its ability to opsonize Escherichia coli. Thymopentin was found to improve neutrophil function on postburn days 2 and 4 and to improve macrophage function on postburn day 4. CP-46,665 was found to improve both macrophage function and opsonization on postburn day 2.