Objective: The aim of this study was to investigate the damage effect of nonylphenol isomer NP42 on mouse macrophage RAW264.7 cells and the underlying molecular mechanism. Methods: The RAW264.7 cells were with various concentration of NP42 for 24 h， then the cell survival rate was detected by 3-(4，5-dimethyl-2-thiazolyl)-2，5-diphenyl-2-H-tetrazolium bromide (MTT) assay， the cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) contents were detected by commercial kits， RT-PCR was used to detect the mRNA expression level of tumor necrosis factor-α (TNF-α) and inducible nitric oxides synthase (iNOS)， Western blot was used to detect the phosphorylation level of p38 mitogen-activated protein kinase (p38 MAPK) and the expression of protein kinase C (PKC). Results: Compared with the Control group， 0.1-10 μmol/L NP42 showed no effect on cell survival， while NP42 extremely decreased cell survival at 100 μmol/L； Moreover， NP42 treatment significantly inhibited the mRNA expression of TNF-α and iNOS， the expression of PKC protein and the content of cAMP in cells. In contrast， NP42 upregulate the content of cGMP in the cells. In addition， NP42 inhibited the phosphorylation level of p38-MAPK. Conclusion: PKC-cAMP pathway and p38 MAPK signaling pathway were involved in nonylphenol isomer NP42 induced damage in RAW264.7 cells， and this should be one of the major mechanisms by which nonylphenol exerted immunotoxic effects in organism.