Objective To investigate the effect of lidocaine on the LPS-induced NF-κB activity in rat peritoneal macrophages. Methods The peritoneal macrophages obtained from male Wistar rats were placed in 12-well plates at 2 × 106 cell/ml after being cultured for 3 days. Each well contained 1 ml of cell suspension. The cells were randomized into control group (group C), LPS group and 3 LPS + lidocaine group S (group LL1.2.3)(n = 10 wells each). In group LPS and LL1,2,3, the cells were exposed to LPS 100 ng/ml. In group LL1,2,3 the cells were exposed to lidocaine 2, 20 200 kg/ml respectively in addition to LPS 100 ng/ml. After being incubated for 24 h, the HMGB1 concentration in the supernatant (by ElISA) and HMGB1 mRNA expression (by RT-PCR)and NF-κB activity in the cells were measured. Results LPS signiticantly increased HMGB1 concentration,HMGB1 mRNA expression and NF-κB activity in the supernatant. Lidocaine treatment significantly attenuated the LPS-induced increase in HMGB1 concentration HMGB1 mRNA expression and NF-κB activity in a dose-dependent manner. Conclusion Lidocaine can inhibit NF-κB activity in the rat peritoneal macrophages and in turn inhibit the synthesis and release of HMGB1.