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Objective To study the early time course of engraftment of human mesenchymal stem cells in fetal sheep heart and determine the relative roles of proliferation and homing in formation of aggregates of human Purkinje fiber cells. Methods The human sheep xenograft model was utilized for these studies. Prior to injection in the preimmune fetus, human cells were labeled with fluorescent dyes to be able to track human cells at early times of engraftment. Results Human stem cells were detected in fetal hearts between 29 and 39 hours after intraperitoneal injection. Engraftment was primarily in the Purkinje fiber system. By 45 hours engrafted human cells had a cardiac phenotype. When two groups of human mesenchymal stem cells, each labeled with a different fluorescent dye, were combined prior to injection, aggregates of human Purkinje fiber cells contained cells labeled with either one dye or the other, no aggregate contained cells labeled with both dyes. Conclusions Human mesenchymal stem cells introduced into fetal sheep rapidly enter the myocardium. The swift differentiation into a cardiac phenotype indicates that the cardiac milieu has a strong influence on the fate of engrafting human mesenchymal stem cells. The absence of any aggregates of human Purkinje fiber cells containing both fluorescent dyes demonstrates that each aggregate of human Purkinje fiber cells is derived from a single mesenchymal stem cell and not from homing of multiple cells to a hotspot.