Ischemia-reperfusion injury (I/R-I), which is unavoidable in liver transplantation, impairs liver regeneration and predisposes to liver failure. The three major mitogen-activated protein-kinases (MAPKs): ERK, p38, and JNK, are critical in the transmission of signals triggered by proinflammatory cytokines, by stress, and by growth factors. JNK and p38α activation have been associated with apoptosis; p38β with cell survival; and ERK with proliferation. Previous studies have demonstrated gender dimorphism in hepatocellular dysfunction after experimental trauma and hemorrhage. Female mice are protected to a much greater extent from I/R-I than male mice. We assessed the effects of 17β-estradiol (17β-E) on liver function, host survival, and cellular activation of MAPK in a murine model of I/R-I in reduced-size livers. C57BL/6 mice were subjected to 45 minutes of warm ischemia (70% of the liver mass). After reperfusion, the nonischemic lobes were excised. Vehicle, 17β-E or the estrogen receptor antagonist ICI-182780, was delivered 1 hour before the injury. We evaluated AST and apoptosis as well as activation of JNK, p38, and ERK. Female mice showed a lower level of hepatocellular injury (AST = 445 ± 82 IU/L) after I/R-I compared with male mice (AST = 1400 ± 210). 17β-E decreased the liver injury in male mice (AST = 522 ± 77), an effect that was partially reversed by ICI-182,780 (910 ± 92). A higher rate of apoptosis was observed in male animals given saline (enrichment factor = 7.22 ± 0.8) versus those treated with 17β-E (5.85 ± 0.3, P < .05). A significant increase in liver regeneration, as assessed by the percentage of liver weight/body weight was demonstrated in females (184% ± 24%) and male mice given 17β-E (168% ± 22%) compared with male mice given vehicle (9% ± 4%). 17β-E significantly down-regulated JNK and p38α activities, whereas I/R-I promoted p38β and ERK activation. These results suggest that the cytoprotective effects of 17β-E on I/R-I to reduced-size livers are associated with selective modulation of MAPK kinases. © 2005 by Elsevier Inc. All rights reserved.