Background: Multiple myeloma (MM) is an incurable malignant neoplasm of plasma cells, in which genetic defects, epigenetic aberrations and bone marrow microenvironment are involved in the pathogenesis. RASSF10 acts as a tumor suppressor gene by methylation in glioma and several other cancers, but its role in MM remains unknown. Methods: In order to explore the role of RASSF10, mRNA expression was detected in MM patients and analyzed with overall survival. Results: Expression of the RASSF10 gene significantly decreased in newly diagnosed MM patients, and was positively correlated with overall survival. RPMI-8226 and OPM-2 cell lines with lower RASSF10 expression were selected for further study. Overexpression of RASSF10 in these two cell lines inhibited proliferation and induced apoptosis. The RASSF10 gene promoter in MM cell lines was hypermethylated, and downregulated after decitabine treatment. Meanwhile, expression of the RASSF10 gene was upregulated. MM cells with overexpression of RASSF10 were injected into nude mice and exerted anti-MM activity in vivo. Conclusions: Low expression of RASSF10 contributed to the proliferation of myeloma cells by hypermethylation of its promoter.