Multiple myeloma (MM) is an incurable heterogeneous disease derived from malignant clonal expansion of plasma cells. The evaluation of prognosis, detection of minimal residual disease (MRD) and treatment of MM are unclear for decades. Recently, Velcade and autotransplantation have been broadly applied to MM patients and achieved better outcomes, but there is yet no effective and universal marker for MRD detection in MM. Both genetic and epigene-tic aberrations play important roles in the pathogenesis and development of cancer. Our preliminary data showed that aberrant promoter methylation of zo-1 and id4 genes was correlated with their gene silencing in several types of hematological malignancies. Therefore, this study was aimed to identify the promoter methylation status of zo-1 and id4 genes in MM and their relationship with the prognosis, MRD and treatment of MM. The methylation status of zo-1 and id4 genes of MM cell lines U266, H929 and IM9 was tested by using MS-PCR; the methylation status of zo-1, id4 gene promoters in bone marrow samples of 20 MM patients and 6 healthy persons was detected by MS-PCR. The results showed that the zo-1, id4 gene in MM cell lines all were methylation positive (complete or partial methylation), the zo-1, id4 gene in samples of 5 healthy persons all were completely unmethylated. The methylation positive rate of zo-1 and id4 genes were 50% and 85% respectively, which were significantly higher than that in normal bone marrow (0%). The coverage rate of zo-1 and id4 gene methylation was 95%. There were no significant differences in the methylation status of both genes among the patients with different heavy chains, different light chains and symptoms. It is concluded that the change of zo-1, id4 genes methylation status occurs in MM patients and has specificity, which may be a new gene marker of MM, methylation analysis of zo-1 and id4 genes may be important for MRD monitoring in patients with MM.