Deficiencies in the immune system that lead to increased morbidity and mortality from infectious complications have been well documented in patients suffering from trauma, malnutrition, sepsis, and thermal injuries. We investigated the potential benefit of immune stimulation for preventing infection in such conditions in an animal model by evaluating three drugs: Corynebacterium parvum, thymopentin (TP-5), and CP-46,665. One-hundred eighty female guinea pigs were rendered immunodeficient by first inflicting a 30% total body surface burn and then placing the animals on diets with calories inadequate to maintain body weight. One half of the animals were then given one of the three immunomodulators on the first, third, and fifth days after burn injury, to try to reverse immunodeficiency. The remaining animals received saline solution injections. Animal responses were evaluated by inserting a clot containing Escherichia coli and Bacillus fragilis into their peritoneal cavity 6 days after burn injury. The animals were followed for 21 days after burn injury. Autopsies on those that died revealed peritonitis and/or pneumonia; autopsies on these that survived showed no pneumonia and there was consistent resolution of peritonitis. TP-5 and CP-46,665, but not C. parvum, significantly improved survival rates and mean survival time in those animals receiving 100 kcal/kg/day. TP-5 and CP-46,665 may be of benefit to the severely stressed, malnourished surgical patient who is at risk of bacterial infection.