AbstractB-1b cells produce IgM natural antibodies against α1-3Galβ1-4GlcNAc (αGal). These can be tolerized by nonmyeloablative induction of mixed chimerism using αGal-positive (αGal+) donor marrow. We assessed the role of CR1/2 in this model for induction of tolerance of B-1b cells. Mixed hematopoietic chimerism was induced in α1-3galactosyltransferase (GalT−/−) and GalT−/−Cr2−/− mice with αGal+ BALB/c marrow donors. Anti-αGal Ab and anti-αGal Ab–producing B cells became undetectable in GalT−/− chimeras, whereas they persisted in chimeric GalT−/−Cr2−/− mice. To determine whether CR1/2 expression on stromal cells and/or hematopoietic cells was critical for B-1–cell tolerance, we generated GalT−/− radiation chimeras in which CR1/CR2 was expressed on either stromal cells, hematopoietic cells, neither, or both. After induction of mixed chimerism from αGal+ allogeneic bone marrow (BM) donors, anti-αGal–producing B cells were rendered tolerant in reconstituted recipients expressing only stromal CR1/CR2. Our results suggest a possible role for follicular dendritic cells that pick up immune complexes via CR1/CR2 receptors in the tolerization of B-1b cells.