Both leptin and interleukin-6 (IL-6) are hypersecreted in acute critical illness, such as sepsis. Leptin is produced by adipocytes, it inhibits appetite and stimulates the sympathetic nervous system, thereby reducing adipose mass. IL-6 is produced by immune cells and adipocytes, it reduces the production of other inflammatory cytokines and stimulates release of acute phase proteins by the liver, participating in the control of inflammation. Leptin inhibits, whereas IL-6 stimulates, the hypothalamic-pituitary-adrenal axis. While high IL-6 levels are associated with poor outcome in critically ill patients, the role of leptin in critical illness and its importance for survival are not known. To examine the relation between IL-6, leptin and cortisol in critical illness, we performed frequent 4 h plasma sampling in eight patients on day 1 of intensive care unit admission for acute sepsis. Sampling was repeated on days 3 and 5 in the five survivors. The levels of all three hormones were markedly elevated; there was a lack of the normal diurnal rhythmicity of leptin and IL-6 and a blunted diurnal rhythmicity of cortisol secretion. A strong negative correlation between mean 24 h plasma IL-6 and leptin was revealed. Although such a relationship could possibly be explained by the negative and positive effects of cortisol hypersecretion on each hormone respectively, a negative correlation between leptin and cortisol was detected, whereas there was no significant correlation between IL-6 and cortisol. Mean IL-6 values were higher (1389.5±644.9 vs. 658.8±250.5) and leptin levels were lower (2.73±1.1 vs. 26.5±11.6) in the non-survivors than in the survivors. These findings suggest that IL-6 is not the principal stimulus of leptin hypersecretion in critically ill patients with sepsis. The negative relation between IL-6 and leptin is of potential importance, as high IL-6 levels have been associated with poor outcome in critically ill patients, and relatively low leptin levels may impair sympathetic system and immune functions.