C57BL/6 mice were subjected to a full thickness scald thermal injury covering 25% of their total body surface area, and thioglycollate elicited peritoneal macrophages (Mphi were isolated 4 days later. Mphi from injured mice produced significantly greater amounts of reactive nitrogen intermediates and tumor necrosis factor-alpha in response to lipopolysaccharide and lipid A. Pertussis toxin (PTX) treatment of Mphi dose-dependently inhibited reactive nitrogen intermediate production in Mphi from sham-treated mice; however, Mphi from injured mice were insensitive to PTX-mediated inhibition. Conversely, tumor necrosis factor-alpha production was enhanced by PTX treatment, with Mphi from injured mice being more sensitive than Mphi from sham-treated mice to this effect of PTX. These results indicate that thermal injury increases Mphi sensitivity to lipopolysaccharide by a mechanism that is both PTX sensitive and PTX insensitive, thereby suggesting a role for G proteins in the modulation of Mphi activity after thermal injury.