Arsenite (As(III)), an effective chemotherapeutic agent for the acute promyelocytic leukemia (APL) and multiple myeloma (MM), might be also a promise for the therapy of other cancers, including the solid tumors. However, the molecular bases of arsenite-induced cytotoxicity in the tumor cells have not been fully defined. In this study, we have disclosed that arsenite effectively induces the apoptotic response in the HepG2 human hepatoma cells by triggering GADD45alpha induction and the subsequent activation of JNKs/AP-1 cell death pathway. However, signaling events relating to GADD45alpha/JNKs/AP-1 pathway activation have not been observed in HL7702 human diploid hepatic cells under the same arsenite exposure condition. Our results thus have illustrated the selective pro-apoptotic role of arsenite in the hepatoma cells by activating GADD45alpha-dependent cell death pathway whereas with little effect on the normal hepatic cells. The approaches to up-regulate GADD45alpha levels might be helpful in improving the chemotherapeutic action of arsenite on certain solid tumors including hepatoma.