As the natural resistance-associated macrophage protein 1 Nramp1 (also known as Slc11a1) modulates Kupffer cell (KC) activation, and KC are responsible for the early phase of warm ischemia/reperfusion (I/R) to the liver, we hypothesized that livers of Nramp1(-/-) mice will be protected from early-phase I/R injury compared with livers of Nramp1(+/+) mice. To test our hypothesis, we induced partial warm ischemia to the livers of Nramp1(+/+) and Nramp1(-/-) mice for 45 min of by clamping the hilum of the median and left lateral lobes, followed by 30 or 60 min of reperfusion. Plasma glutamate oxaloacetate transaminase (pGOT) activity and tumor necrosis factor alpha (TNF-alpha) levels were measured, and liver sections were stained for polymorphonuclear leukocyte (PMN) accumulation. After 45 min of ischemia and 30/60 min of reperfusion of Nramp1(+/+) and Nramp1(-/-) mice livers, we found significant increases in plasma pGOT activity and TNF-alpha levels in Nramp1(+/+) mice at 30 and 60 min of reperfusion, respectively, compared with sham controls and all Nramp1(-/-) mice. A significant accumulation of PMNs was also found in livers of Nramp1(+/+) mice at 60 min of reperfusion compared with all other groups. We have shown that disruption of the Nramp1 gene attenuates I/R injury to the mouse liver during the early phase of warm I/R injury. An increased understanding of the role played by Nramp1 is particularly important in the liver, as this organ is subjected to a wide variety of injuries during hemorrhagic shock, partial resections, and transplantation.