Leptin, a newly discovered adipose tissue-derived weight-reducing hormone, is increased in acute inflammation and may be involved in the anorexia and wasting syndrome associated with infection. To determine whether this hormone responds to an acute inflammatory stimulus, plasma leptin concentrations were measured in 12 healthy subjects after intravenous administration of endotoxin. These subjects were randomized to receive concurrently ibuprofen or placebo normal saline (6 in each group). Endotoxin administration resulted in fever, leukocytosis, and an increase in plasma levels of the stress hormones adrenocorticotropic hormone (3.2 +/- 0.3 to 132.6 +/- 75.5 pmol/L, P = .001) and cortisol (431.6 +/- 44 to 796.9 +/- 99 mmol/L, P = .001). Plasma leptin levels, however, did not change significantly from baseline values after administration of endotoxin (0 h: 6.9 +/- 3.1 ng/mL; 6 h: 6.0 +/- 2.2; 24 h: 6.5 +/- 2.8). While ibuprofen suppressed fever and symptoms associated with endotoxemia, it had no effect on the plasma levels of leptin. In conclusion, acute experimental human endotoxinemia is not associated with acute changes in circulating leptin levels.