Critical illness and severe inflammation are catabolic states characterised by breakdown of tissue and protein stores, by increased levels of free fatty acids, and by insulin resistance. These metabolic features contribute to morbidity and mortality. Growth hormone and insulin are the two major anabolic hormones. The present study was designed to test whether increased levels of free fatty acids (i) inhibit growth hormone secretion and (ii) induce insulin resistance during acute endotoxin exposure in a porcine model of critical illness. We studied 20 pigs for 6 h during combined anaesthesia and endotoxin infusion and a hyperinsulinaemic glucose clamp to control glucose, insulin, and free fatty acid concentrations. Pigs were randomised to two different continuous infusion rates of Intralipid resulting in different, sustained, and elevated free fatty acid concentrations (1.63 mmol l(-1) vs. 0.58 mmol l(-1), p=0.0002). Concomitantly, we observed reduced growth hormone concentrations in the group with high free fatty acid concentrations (3.5 ng ml(-1) vs. 6.6 ng ml(-1), p<0.003). No difference in insulin sensitivity, measured as the glucose infusion rate necessary to maintain euglycaemia, was observed. We conclude that high levels of free fatty acids reduce circulating growth hormone concentrations in porcine endotoxaemia; this probably constitutes a negative feedback mechanism whereby growth hormone induced-stimulation of free fatty acids release inhibit growth hormone secretion. This mechanism may further contribute to protein loss in critical illness. We found no evidence that the increment of plasma free fatty acids between groups contribute to insulin resistance in critical illness.