Kupffer cells are thought to mediate most of the deleterious effects of liver ischemia‐reperfusion injury. The role of liver T cells and the impact of resident cell deactivation by interleukin 10 (IL‐10) have never been addressed. Using a model of ex vivo liver cold ischemia and reperfusion, we assessed liver injury, tumor necrosis factor (TNF) and interferon gamma (IFN‐γ) release from livers of balb/c mice, nude mice, nude mice reconstituted with T cells, and gadolinium balb/c pretreated mice. The anti‐inflammatory cytokine IL‐10 was then used to define the best strategy of administration potentially able to modulate ischemia‐reperfusion injury. For this purpose IL‐10 was administered to the donor before liver harvesting, in the preservation medium during cold ischemia or during reperfusion. TNF and IFN‐γ were released time dependently and paralleled liver injury after reperfusion of cold preserved livers. Reperfused livers from nude or gadolinium pretreated mice disclosed a dramatic decrease in TNF and IFN‐γ release. Tissue injury was reduced by 51% in the absence of T cells and by 88% when Kupffer cells were deactivated. This effect was reverted by T‐cell transfer to nude mice. Only donor pretreatment with IL‐10 or IL‐10 infusion during reperfusion led to a significant decrease in liver injury, TNF, and IFN‐γ release (−66% or −41%, −95% or −94%, and −70% or −70%, respectively). In conclusion, liver resident T cells are critically involved in cold ischemia‐reperfusion injury and pretreatment of the donor with IL‐10 decreases liver injury and the release of T‐cell– and macrophage‐dependent cytokines.