Background. Previous clinical reports have documented multisystem organ injury after hepatic cryoablation. We hypothesized that hepatic cryosurgery, but not partial hepatectomy, induces a systemic inflammatory response characterized by distant organ injury and overproduction of nuclear factor κB (NF-κB)-dependent, proinflammatory cytokines. Methods. In this study, rats underwent either cryoablation of 35% of liver parenchyma or a similar resection of left hepatic tissue. Serum tumor necrosis factor-α and macrophage inflammatory protein-2 levels and NF-κB activation were assessed by electrophoretic mobility shift assay at 30 minutes 1, 2, 6, and 24 hours after either procedure. Results. Cryoablation of 35% of liver (n = 22 rats) resulted in lung injury and a 45% mortality rate within 24 hours of surgery, whereas 7% treated with 35% hepatectomy (n = 15 rats) died during the 24 hours after surgery (P < .05, cryoablation vs hepatectomy). Serum tumor necrosis factor-α and macrophage inflammatory protein-2 levels were markedly increased in rats (n = 10 rats) 1 hour after hepatic cryoablation compared with rats that underwent partial hepatectomy (P < .005). We evaluated NF-κB activation by electrophoretic mobility shift assay in nuclear extracts of liver and lung after cryosurgery and found that NF-κB activation was strikingly increased in the liver but not the lung at 30 minutes and in both organs 1 hour after cryosurgery, and returned to baseline in both organs by 2 hours. In rats undergoing 35% hepatectomy, no increase in NF-κB activation was detected in nuclear extracts of either liver or lung at any time point. Conclusions. These data show that hepatic cryosurgery results in systemic inflammation with activation of NF-κB and increased production of NF-κB- dependent cytokines. Our data suggest that lung injury and death in this animal model is mediated by an exaggerated inflammatory response to cryosurgery.