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The signaling lymphocytic activation molecule family 3 (SLAMF3) is highly expressed on plasma cells from patients with multiple myeloma (MM) and induces high malignant potential by ERK signaling mediated via the interaction with adaptor proteins SHP2 and GRB2. This study focused on the single-nucleotide polymorphism (SNP) of the SLAMF3 gene (rs509749, 1804A>G, M602V) in MM. The SNP G allele was a major type, and the frequencies of the GG, GA, and AA genotypes were 61.8%, 29.4%, and 8.8%, respectively, in patients with MM, which was almost the same as in healthy the control group in the Japanese population. Interestingly, patients with GG genotypes had significantly shorter overall survival times than patients with GA/AA genotypes. Consistent with those results, SLAMF3-overexpressing KMS-34 cells with the G allele (V 602 ) had higher cell proliferation potential and were more resistant to anti-MM agents than those with the A allele (M 602 ). When those cells were subcutaneously inoculated into NOG mice, tumor sizes in mice receiving V 602 cells rapidly increased, and survival was significantly shorter than in mice injected with M 602 cells. Furthermore, SLAMF3 V 602 molecules bound more tightly to SHP2 and GRB2, with increased SHP2 and ERK phosphorylation compared with M 602 cells. The mRNA expression of cell cycle-related genes (CCND1 and CCNE1) and anti-apoptotic genes (BCL2L and p21) was increased in V 602 cells compared with M 602 cells. The results thus suggested that the G allele of SLAMF3 SNP rs509749 may be associated with MM disease progression., Competing Interests: Conflict of interest disclosure The authors declare that they have no conflicts of interest., (Copyright © 2020 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)