|Sodium arsenite (As) affects many cellular responses such as apoptosis, cell proliferation, differentiation, angiogenesis and increased risk of cancer. We hypothesis that sodium arsenite interfere proinflammatory cytokine factor (TNF-alpha-induced apoptosis process via EGFR and MAPK activation. Epidermal growth factor receptor (EGFR) pathway is mainly growth factor protein that had been responded to arsenic exposure as well as pro-inflammatory cytokines such as TNF-alpha, interleukin-6 (IL-6) in many cancers. However, the effect of arsenic interfere the molecular functional of EGFR under TNF-alpha stimulating factor are poorly understood. In this study, we studied the biological phenomenon of cells-exposed includes cell toxicity, mitochondrial membrane changing, reactive oxygen species products (ROS) in HeLa cell lines and the relative protein in immunoblotting analyses to investigate how sodium arsenite affect to TNF-alpha regulated the activation of EGFR and MAPK leads to apoptosis process. The results of MTT assay and annexin V/PI in fluorescence microscopy indicated sodium arsenite increased the potential of TNF-alpha-induced cell death than only TNF-alpha stimuli but these toxic did not involve ROS products. The potential of mitochondrial membrane of TNF-alpha was slightly inhibited by MAPK and EGFR inhibitors but not As/TNF-alpha and As, indicating that As controlled a role in mitochondrial membrane better than TNF-alpha. Arsenite also regulated EGFR and MAPK phosphorylation in time-dependent which had been reported in response to TNF-alpha. Exposure of As/TNF-alpha had increased JNK, p38 phosphorylation and some residues of EGFR phosphorylation, in addition to enhance the cleavage of caspase-3,-7,-8,-9 and PARP. The chemical inhibitors of MAPK family (JNK, p38 and ERK) and EGFR used to detect the interference of As/TNF-alpha. TNF-alpha regulated higher signal of JNK and p38 phosphorylation and cleavage of caspase-3,-7 and parp after suppressed with SP600125 which in contrast, As/TNF-alpha enhanced cleavage of caspase-8 in pretreatment of SB203580. It’s indicated that TNF-a-down regulated p38 and JNK phosphorylation to inhibit effect of apoptosis (anti-apoptosis), For As/TNF-alpha exposure, arsenite effects to increase cleavage of caspase-8 which as an initiator caspase, closely upstream signal from extrinsic pathway. In contrast, JNK inhibitor reduced cleavage of caspase-9 on As/TNF-alpha-exposed that different with TNF-alpha reaction. These results discussed that each of stimulator effects regulated JNK phosphorylation and enhanced after together stimulate, which JNK activation had an important role in both, arsenite phosphorylated JNK and leads to apoptosis via mitochondrial cytochrome c release pathway, reversely TNF-alpha mediated JNK to recruit dead receptors and prevent apoptosis. Therefore, arsenite had interfered the signal transduction of TNF-alpha in apoptosis proteins that mediated two pathway reaction related JNK and p38 signaling pathway which could be explained the information of cellular communication network from cytokine and chemical carcinogenesis.