We evaluated the effects of hemorrhagic shock/resuscitation (S/R) on hepatic reticuloendothelial system function, using an in vivo assay that discriminantly quantitates its two essential components, phagocytic clearance and phagocytic killing of double-labeled Escherichia coli injected intravenously. Rats were subjected to hemorrhagic shock at mean arterial pressure at 50 +/- 5 torr for 2 h, resuscitated, and survived. Hepatic phagocytic clearance was significantly decreased immediately following and 6 h after S/R, compared with sham-shocked rats, but recovered to normal levels after 24 h. Although hepatic killing efficiency was increased initially, and transiently depressed 6 h later, it was strikingly upregulated after 24 h. As a consequence, net hepatic killing was transiently suppressed at 0 and 6 h, but upregulated after 24 h. Pre-treatment with proinflammatory agonists, including endotoxin, IFN-gamma, or IFN-gamma + TNF-alpha enhanced both hepatic killing efficiency and net hepatic killing. These observations suggest that although hepatic killing function is initially impaired after the onset of S/R, it is strikingly upregulated 24 h later, simulating both the initial immunosuppression, and the later hyperinflammatory response to systemic S/R that could lead to multiple organ dysfunction syndrome.