Peripheral vasodilation is a common feature of warm heart surgery and creates clinical concerns when pressor agents become necessary because of the potential for some of these drugs to adversely affect flow through newly engrafted arterial and venous bypass conduits. The possible role of a temperature-dependent production of cytokines in the pathogenesis of this vasodilation was investigated in a two-part study. In part I, lipopolysaccharide-activated peritoneal rabbit macrophages (5 x 106/ml) were incubated at 30° or 37° C up to 9 hours and the concentration of tumor necrosis factor released in the supernatant was serially measured by a bioassay. Tumor necrosis factor production was found to increase over time for each of the two temperatures of incubation but was significantly higher throughout the observation period in normothermic experiments than in those done at 30° C. Part II was a prospective clinical study involving 30 patients who underwent either cold (core temperature 28° to 30° C, n = 15) or warm (37° C, n = 15) cardiopulmonary bypass and in whom serum levels of tumor necrosis factor α, interleukin-1β, and interleukin-6 were measured by enzyme-linked immunosorbent assays at 2, 4, 10, and 24 hours after bypass. Cytokine levels were found to be consistently higher in patients having normothermic bypass. Differences between the two groups were significant 2 hours after bypass for tumor necrosis factor α and interleukin-6 (p < 0.02 and p = 0.0001, respectively) and 4 and 10 hours after bypass for interleukin-1β (p < 0.01 and p < 0.04, respectively). The incidence of vasodilation necessitating vasopressor support was twofold higher in the normothermic group (six patients versus three in the hypothermic group). Taken as a whole, patients supported by pressor agents had significantly higher cytokine levels after bypass than those who did not require pressor therapy. Our results suggest that vasodilation occurring with warm heart operation is, at least partly, mediated by a temperature-dependent release of cytokines. Vasodilation might therefore be mitigated by simply allowing the core temperature to drift during bypass. Our recent clinical experience suggests that this 'tepid' heart surgery (32° to 34° C) effectively blunts most of the vasodilatory response to strictly normothermic bypass without compromising maintenance of myocardial aerobiosis during arrest.