Objective To establish a stable, effective, and reproducible acute promyelocytic leukemia model in severe combined immunodeficient ( SCID) beige mice using acute myelocyte HL60 and adriamycin ( ADR)?resistant HL60/ ADR cell lines. Methods Female SCID beige mice (4 – 5 weeks old) were divided randomly into one control group and four model groups with three mice in each group. After X?ray irradiation, SCID mice received 1 × 107 (M1 group) or 5 ×106 (M2 group) HL60 cells, or 1 × 107 (M3 group) or 5 × 106 (M4 group)HL60/ ADR cells via tail vein injection. The white blood cell (WBC) count and positive rate of promyelocytes in peripheral blood were dynamically monitored by detecting cells expressing CD33 using flow cytometry. Morphological examination and histopathological assays were employed to confirm promyelocyte infiltration into organs (liver, spleen, and kidneys). Results The four model groups displayed abnormal behaviors of tremors, retardation, and piloerection. The two high dose model groups experienced significant weight loss compared with the two low dose model groups ( P < 0.05). Moreover, the four model groups had significantly lower body weights than the control group ( P <0.01). At day 32, survival rates of M1 and M3 groups were 33% and 67%, respectively. All mice in M2 and M4 groups survived. The WBC count in peripheral blood declined after X?ray irradiation. At day 28 after inoculation, the peripheral blood WBC counts of the four model groups were significantly higher than that in the control group ( P <0.01). At day 28, the leukemic cell percentage of the M3 group was the highest compared with the other three model groups ( P <0.05). The rates of CD33?positive cells in flow cytometric analysis of the four model groups were higher than that in the control group at day 28, but there were no significant differences between the four model groups. Morphological examination and HE staining of tissue biopsies demonstrated a large number of promyelocytes in the spleen and liver. Conclusions The human acute leukemia SCID beige mouse model was successfully established by tail vein injection of 5 × 106 or 1 × 107 HL60 or HL60/ ADR cells. This model mimics the biological characteristics of acute myeloid leukemia. The survival period of the high dose SCID beige mouse model was short with a median survival time of about 29 days.