Although neutrophils have been implicated in the hepatic injury elicited by gut ischemia/reperfusion (I/R), the contribution of other leukocyte populations to this injury process remains unclear. The objective of this study was to determine whether lymphocytes contribute to gut I/R-induced microvascular dysfunction and inflammatory responses in the liver. Intravital videomicroscopy was used to monitor leukocyte recruitment, the number of nonperfused sinusoids and pyridine nucleotide (NADH) autofluorescence in livers of wild-type, SCID, and interferon-γ (IFN-γ) knockout mice exposed to 15 min of gut ischemia and 1 h of reperfusion. In wild-type mice, gut I/R elicited significant increases in the number of stationary leukocytes, nonperfused sinusoids, NADH autofluorescence (indicating hypoxia), and elevated plasma alanine aminotransferase (ALT) and TNF-α levels. All of these responses were profoundly attenuated in SCID mice, while only some of the responses (in the midzonal region) were blunted in IFN-γ knockout mice. Reconstitution (24 h before ischemia) of the circulating lymphocyte pool with T-cell enriched splenocytes, but not T-cell deficient (from nude mice), CD4⁺T-cell depleted splenocytes or splenocytes derived from IFN-γ knockout mice, allowed the SCID mice to respond to gut I/R in a manner similar to wild-type mice. Some of the responses were restored following reconstitution with CD8⁺T-cell depleted splenocytes. These findings implicate CD4⁺Tlymphocytes and IFN-γ in the hepatic microvascular dysfunction and inflammatory cell accumulation elicited by gut I/R.