Suppressor of cytokine signaling 3 (SOCS3) was reported as a feedback inhibitor of cytokine receptor signaling by inhibiting the JAK-STAT signal transduction pathway. We sought to test the anti-endotoxic septic shock effect of liposome mediated gene delivery of SOCS3 in a lethal endotoxic shock mouse model. BALB/c mice were injected intraperitoneally with 200 μg pcDNA3.1-SOCS3 cationic liposomes, while pcDNA3.1-IL-10 and empty vector as positive and negative control respectively. Forty-eight hours after gene delivery, mice were challenged with 4 μg of E. coli 0127:B8 LPS and 18 mg D-GalN administered i.p. 90 min later, serum TNF-α level was determined. Survival over the next 48 h was evaluated. Peritoneal macrophages from survival mice were stimulated in vitro with 1 μg/ml LPS for 18 h, and the supatants were harvested for determination of the amount of TNF-α. We found that gene delivery of SOCS3 significantly increase the mouse survival rate from 27.8 ± 9.6% of control group to 61.1 ± 9.6% (p ＜ 0.01). In comparison with control group (218 ± 13 pg/ml) and sham delivery group (219 ± 22 pg/ml), gene delivery of SOCS3 reduced the level of serum TNF-α (68 ± 9 pg/ml) significantly (p ＜ 0.01). Furthermore, gene delivery of SOCS3 displayed the capacity of prevention of tolerance of peritoneal macrophages to LPS. These findings suggest that gene delivery of SOCS3 mediated by liposome is a promising approach for endotoxic septic shock treatment. Cellular & Molecular Immunology.