The aim of this study was to explore the effect of arsenic trioxide (As(2)O(3)) on the methylation status of socs-1 gene in multiple myeloma cell lines U266, RPMI8226. The cell viability was assayed by MTT method. The methylation status of socs-1 gene was detected by methylation specific PCR. The expression of socs-1 gene mRNA was determined with real-time PCR. The cell apoptosis was analyzed by flow cytometry. The results indicated that hypermethylation of CpG island of socs-1 gene was observed without expression of socs-1 in myeloma cell lines U266, RPMI8226. The expression of socs-1 gene mRNA in each myeloma cell line increased significantly after exposure to As(2)O(3) for 72 hours as compared with the cell lines of wild type (p0.05). And cell proliferation was significantly inhibited, both early apoptosis and later apoptosis ratios increased in dose-dependent manner. It is concluded that As(2)O(3) may induce socs-1 demethylation and up-regulate the expression of the gene. This study provides a new thought and direction for exploring possible mechanism of cell apoptosis induced by As(2)O(3) and multiple myeloma treatment by As(2)O(3).