Introduction: Hepatic cryoablation produces acute lung injury, with activation of NF-κB in the remnant liver and lungs, production of chemokines, and pulmonary neutrophilic infiltration. Activated complement stimulates NF-κB and cytokine secretion from Kupffer cells. Using this model of liver ischemia-reperfusion in a transgenic mouse, we examined whether complement depletion reduces lung injury. Methods: HLL mice (5' HIV-LTR-Luciferase gene; 5' HIV-LTR is an NF-κB-dependent promoter) underwent partial volume hepatic cryoablation and were sacrificed at 4 or 24 hours postoperatively (N=8 each group). Serial preoperative, IP-dosing of cobra venom factor (CVF) produced total complement depletion; control animals received PBS. Pulmonary CXCL1 chemokine production was measured with ELISA and NF-κB activation by ex vivo luciferase assay. Inflammatory response was quantified using myeloperoxidase (MPO) activity, a reflection of neutrophil content. Data were analyzed by ANOVA and expressed as mean ± SE. Results: CVF treatment reduced serum C3 levels >99% relative to control. After hepatic cryo, NF-κB activity increased in the non-ablated liver remnant by 4 hours in both control (119±23) and CVF-treated mice (118±15) from baseline (0.66±0.09 RLU/µg protein, p<0.0001). In the lung, NF-κB activity increased post-ablation, with substantially more upregulation from baseline observed in C3-depleted mice (Fig). Likewise, chemokines were higher in C3-depleted mice relative to controls (KC: 493±43 vs 269±29 pg/mg protein, p<0.001; MIP-2: 171±29 vs 64±13 pg/mg protein, p<0.0001). At 4 hours, lung MPO did not significantly differ from baseline in controls but was elevated in CVF-treated mice (0.39±0.05 vs 0.28±0.02, p=0.04). Conclusions: Complement depletion resulted in increased pulmonary inflammation following liver cryo-injury via a relative upregulation of NF-κB activity. Activated complement is not the initial pro-inflammatory stimulus in the liver. Downstream components of the complement cascade may ameliorate the systemic inflammatory response.