Sufentanil is a synthetic µ-opioid receptor agonist frequently used in anesthesia and critically ill patients. To evaluate the effects of sufentanil on the inflammatory, neuroendocrine, and metabolic responses to endotoxin, we studied six dogs during saline infusion (control), during sufentanil infusion (1.5 µg · kg¹ · h¹), after endotoxin injection (1.0 µg/kg iv), and during combined endotoxin and sufentanil administration. The rate of appearance of glucose was determined by infusion of [6,6-²H₂]glucose. Sufentanil depressed the endotoxin-induced increase in body temperature (36.9 ± 0.3 vs. 40.6 ± 0.5°C, P < 0.05). Sufentanil depressed the tumor necrosis factor (TNF) response to endotoxin by ~60% (P < 0.01) but increased the interleukin-6 (IL-6) response by ~70% (P < 0.01). Sufentanil per se induced a transient neuroendocrine activation. Sufentanil also increased plasma concentrations of insulin and catecholamines after endotoxin (P < 0.05 vs. endotoxin alone) and increased plasma glucose levels by ~36% (from 6.1 ± 0.1 to 8.3 ± 0.6 mmol/l, P < 0.05 vs. endotoxin alone). Endotoxin stimulated glucose production transiently by 95% (24.2 ± 3.2 vs. control 12.4 ± 1.0 µmol · kg¹ · min¹, P < 0.05). Paradoxically, sufentanil inhibited this endotoxin-induced stimulation of glucose production (P < 0.05 vs. endotoxin alone). In conclusion, sufentanil modulates the response to intravenous endotoxin by dissociating the TNF and IL-6 response, increasing insulin and catecholamine levels, and depressing the increase in glucose production. Therefore, opiates alter inflammatory, endocrine, and metabolic regulation in endotoxemia.