Nitric oxide(nitrogen monoxide, NO) plays important physiological roles, but excessive generation can be toxic. NO is present in cigarette smoke at up to 1,000 ppm, and probably represents one of the greatest exogenous sources of NO to which humans are exposed. We investigated whether cigarette smoking reduces the production of endogenous NO and whether it influences the action of lipopolysaccharide(LPS) to induce nitric oxide synthase activity in mouse brain. Mice(C57BL6/J) were exposed to cigarette smoke for 8 weeks. LPS was injected intraperitoneally in single or combination with the exposure to cigarette smoke. Six hours after the injection of LPS, mice were sacrificed and sera and brains were collected. Serum concentrations of nitrate and nitrite were not charged by 4-week smoke exposure, but were significantly increased by 6 and 8 weeks of smoke exposure. Interestingly, cigarette smoke reduced the elevation in serum nitrate and nitrite concentrations produced by LPS after 4-week smoking exposure. NO synthase(NOS) activity in brain was upregulated by LPS-administration. However, cigarette smoke exposure remarkably and consistently decreased the LPS-induced activity in mouse brain. This result suggests that cigarette smoking may affect against overproduction of the endogenous NO by LPS through the inhibition of NOS activity induced by LPS in brain or by modulation of the LPS action for the induction of NOS activity. We also suggest the possibility that the exogenous NO evolved in cigarette smoke enables feedback inhibition of NOS activity or other possibility that it attenuates the toxicity of endotoxin LPS in vivo by unknown mechanisms, which should be further studied.