Objective To explore the role of mitogen-activated protein kinase(MAPK)in lipopolysaccharide(LPS)-induced iNOS expression and NO production in rat Schwann cells by the use of inhibitors PD98059 selective for extracellular signal-regulated kinase 1/2(EPK1/2), SB202190 for P38 MAPK and SP600125 for the c-Jun NH_2-terminal kinase (JNK). Methods Schwann cells were pretreated with PD98059 (30, 50, 70?mol/L), SB202190 (10, 20, 40?mol/L) and SP600125 (10, 30, 50?mol/L) at the indicated concentrations for 1 hour before the stimulation with LPS (10mg/L) for 4 hour. The estimation of iNOS mRNA, IL-6 mRNA and TNF-? mRNA was performed by RT-PCR; the changes of iNOS protein expression were investigated by Western blotting. The NO level was observed with measurement of nitrite in the cell culture medium. Results LPS could significantly activate MAPK signal pathway and lead to the expression of iNOS and NO production. The iNOS expression and NO production induced by LPS stimulation were significantly inhibited by the three highly specific inhibitors of MAPK. In addition, the inhibitors decreased LPS-induced the expression of IL-6 mRNA and TNF-? mRNA. Conclusion Activation of MAPK pathway is involved in iNOS expression and NO production in rat Schwann cells, and the inhibition of the signal transduction pathway can be effective to reduce the production of iNOS and NO, which may be a useful strategy against inflammatory and immune reaction after peripheral nerve injury.