We have developed a murine model of in utero transplantation in nonanemic, beta-thalassemic mice to study chimerism, tolerance, and changes in hematological parameters in response to cytokines and postnatal boosts with donor cells. We have documented improved survival of homozygous fetuses by 40% as compared with controls. Low-level, mixed chimerism was improved by postnatal cytokine therapy and boosts and was associated with improvement in hemoglobin levels, reticulocyte counts, and iron stores. Cytotoxicity assays demonstrated higher responses to donor cells in control mice as compared with in utero transplanted animals (at 50:1 effector to target ratios, transplanted mice showed 8.66% target lysis and control mice showed 51.85% target lysis, P=0.0003), indicating tolerance. The combination of prenatal tolerance to allogeneic cells with postnatal boosts in primed hosts may become an effective, nontoxic strategy for the improvement of hemolytic anemia in beta-thalassemic patients.