To study the role of Kupffer cells (KC) as a cellular source of proinflammatory cytokines in hepatic ischemia/reperfusion, Sprague-Dawley rats were subjected to 20 min global hepatic ischemia. Sham-operated animals served as controls. Blood levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha), and interleukin 6 (IL-6) were determined after 10, 30, 60, 120, and 240 min of reperfusion and compared with spontaneous cytokine release by KC isolated after 60 min of reperfusion. Hepatic ischemia/reperfusion resulted in an enhanced (p < .01) spontaneous release of TNF-alpha (+482%), IL-1 alpha (+33%), and IL-6 (+175%) by KC. Kinetic analysis of cytokinemia revealed an early increase (p < .01) of TNF-alpha and IL-1 alpha within minutes upon reperfusion, while an elevation of IL-6 serum levels was observed with a delay of 2 h. Early cytokinemia was associated with dysfunction/injury of the liver, lung, and kidney after 4 and 24 h of reperfusion, respectively. These data indicate that hepatic ischemia/reperfusion results in Kupffer cell activation and increased cytokine levels, which may produce systemic inflammation and may be responsible for tissue injury locally and on remote sites.