To date, 16 in utero hematopoietic stem cell (HSC) transplants for diseases other than immunodeficiency disorders have been reported. No therapeutic level of engraftment was detected in 15 of these transplants. To overcome engraftment failure, we transplanted a very large number (5 billion paternal CD34+ cells/kg) of HSCs to a fetus with leukodystrophy during the first trimester of gestation. As reported previously, the fetus died in utero 7 weeks after the procedure and the cause of death appeared to be overwhelming donor engraftment. In the present investigation, we developed a human-murine chimera model to test for the optimal donor cell dose for human in utero transplantation. We found a strong correlation between the level of donor engraftment in three human fetuses transplanted for leukodystrophy during the first trimester of gestation and the results of parallel xenotransplants of the same human donor cells using the NOD/SCID mouse model. This small animal model appears to predict both extremes of hyperengraftment (seen in the first human fetus transplanted) and engraftment failure (seen in the second and third human fetuses transplanted in utero). These and future correlated clinical and laboratory assay results may be useful for the development of in utero transplants for a variety of congenital disorders.