The aim of this study was to investigate factors influencing the engraftment potential of acute myeloid leukemia (AML) CD34+ cells in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice. We examined the relationship between engraftment, CXCR4 expression on CD34+ and CD34+CD38- cells, and patient (Pt) clinical/laboratory characteristics in 44 samples from 11 Pts. Engraftment, evaluated by Southern blot and CD45 flow cytometric analyses, was observed in murine bone marrow of 6 of 11 Pt samples, ranging from 0.1% to 73.9% by Southern blot and from 0.1%-36.8% by flow cytometry. Poor Pt prognosis was inversely correlated with engraftment; the median overall survival was 95.9 weeks for Pts whose cells did not engraft and 26.1 weeks for those whose cells did engraft (p = 0.012, log-rank test). No other clinical/laboratory variable predicted engraftment. No correlation between the level of CXCR4 expression on AML cells and engraftment was observed. Cells with virtually absent CXCR4 expression were able to engraft, and cells from two Pts with high expression levels of CXCR4 did not engraft. Furthermore, anti-CXCR4 antibody failed to block the engraftment of AML cells into NOD/SCID mice. In conclusion, we demonstrated that CXCR4 is not critical for the engraftment of AML CD34+ cells in NOD/SCID mice. The model may, however, reflect the clinical course of the disease.