Background. There is increasing evidence that injury to the liver can precipitate or exaggerate lung injury. We have previously shown that hepatic cryoablation (cryo) causes activation of nuclear factor (NF)-κB, cytokinemia (tumor necrosis factor-α, Mouse Macrophage Inflammatory Protein-2 [MIP-2]), and lung inflammation in transgenic HLL (5′HIV-LTR-Luciferase gene) mice and in Sprague-Dawley rats. It has been reported that BALB/c mice are susceptible to traumatic injury and are active immune responders. We tested whether activation of NF-κB and the development of multiple-organ inflammation in response to hepatic injury from 35% cryo were demonstrable in the BALB/c mouse. Methods. BALB/c mice (n = 9) were anesthetized, and midline laparotomy was performed. Cryoablation was performed with careful isolation of adjacent structures to avoid inadvertent organ injury to the gastrointestinal tract. A freeze-thaw cycle of the left lobe of the liver was induced, encompassing approximately 35% (by weight). Animals were sacrificed at 1, 2, 4, and 24 h after cryoablation. Serum was collected via IVC puncture and liver, lungs, and kidneys were harvested and freeze-clamped. Two animals were sacrificed without undergoing cryo surgery to serve as a baseline control. NF-κB activity was monitored by electrophoretic mobility shift assays. MIP-2 levels and Mouse KC levels from tissue and serum were measured using enzyme-linked immunosorbent assay. Organs were submitted for histological review. We characterized lung inflammation induced by cryosurgery by measuring total and differential cell counts in lung lavage fluid 4 h after hepatic cryoablation. Results. After cryo, NF-κB activation was demonstrated in the 1, 2, and 4-h time points by electrophoretic mobility shift assay in the liver and lungs. Mouse KC and MIP-2 levels increased from baseline, peaked at the 4-h time point, and returned to baseline after 24 h in both liver and lung. Lung lavage 4 h after cryoablation showed increased total cells and neutrophilic lung inflammation. Conclusions. BALB/c mice demonstrate evidence of multi-organ inflammation in response to 35% hepatic cryo. These data demonstrate that this model provides for assessment of liver-mediated multi-system inflammation after direct liver injury.