Objective · To investigate the effect of mammalian target of rapamycin (mTOR) inhibitor rapamycin on acute myeloid leukemia (AML) with DNA methyltransferase 3A (DNMT3A) R882 mutation in momodel. Methods · AML cell line OCI-AML3 cells with DNMT3A R882 mutation were cultured with the treatment of rapamycin or DMSO, and then these cells were injected into the tail vein of sublethally irradiated NOD/SCID mice, respectively. The disease progression was monitoredblood routine examination and flow cytometry analysis of CD45+, OCI-AML3 cells, in peripheral blood. Survival time was recorded. Samples bone marrow, spleen and liver were harvested for flow cytometry analysis and pathological examination. Results · The increasing trend of peripheral leukocytes in the rapamycin treated group was obviously slower than that in the DMSO treated group. The proportion of peripheral blood CD45+ cells in the rapamycin treated group was (4.44±2.58)% (1 week after transplantation) and (34.42±13.64)% (2 weeks after transplantation), which were lower than (16.71±8.96)% and (51.55±5.36)% in the DMSO treated group in the same period, respectively. The median survival time of the rapamycin treated group (27 d) was significantly longer than that of the DMSO group (23 d). The ratios of CD45+ cell infiltration in bone marrow, spleen and liver of the rapamycin treated group were all less than 5%, which were significantly lower than those [(51.32±27.81)% in spleen and (50.03±28.74)% in liver] of the DMSO treated group. Compared with the DMSO treated group, the spleen size of the mice was significantly smaller, and the spleen infiltration and structural damage were significantly alleviated in the rapamycin treated group. Conclusion · Rapamycin shows effective inhibition on the progression of AML with DNMT3A R882 mutation in NOD/SCID momodel.