The present study examined the potency of smooth or rough Pasteurella haemolytica lipopolysaccharide infusion (LPS, 24 ng kg-1 min-1 for 500 min) on plasma cyclic-nucleotides and several free fatty acids (FFA) in calves. Both smooth or rough LPS increased plasma cAMP immediately to its maximum at 1 h of infusion, whereas plasma cGMP levels rose slowly and peaked 12 h later. The increases in cAMP levels were more prolonged for smooth LPS than rough LPS. The maximum plasma cAMP rise coincided with increases of several plasma FFA. Rough LPS increased plasma oleic greater than palmitic greater than stearic greater than linoleic acids in the second hour and reached their steady state levels between 2 h of infusion and 5 h post-infusion. Thereafter, oleic acid remained maximally elevated, while stearic acid decreased and other FFA returned to baseline. Smooth LPS had no effects on palmitic and stearic acids, but elevated oleic acid in an essentially similar manner to rough LPS and increased linoleic acid initially at 5 h, followed by decreases throughout post-infusion. These results demonstrate that endotoxemia produces early marked elevations in plasma cAMP, a gradual rise in plasma cGMP and disproportionate increases in several plasma FFA. The data also demonstrate that smooth and rough LPS differ in their abilities to increase plasma cAMP and FFA and these may be attributed to differences in their in vivo mechanisms of action. The study suggests that cAMP and cGMP may mediate actions of endotoxin at the cellular level and that differences exist in release and/or utilization of each FFA at different stages of endotoxemia.