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By using alpha-galactosyl transferase knockout (GT-/-) mice, which make natural alphaGal-reactive antibodies, we examined the role of complement receptors in the production of alphaGal-specific antibodies. GT-/- mice were crossed with complement receptor 2 loci knockout mice to generate double knockout (DKO) mice. alphaGal-specific natural antibodies were detectable by enzyme-linked immunosorbent assay in the serum of GT-/- mice by 9 weeks of age. In contrast, only low titers of alphaGal-specific natural antibodies were detectable only in the serum of older DKO mice. Serum titers of alphaGal-reactive antibodies in GT-/- mice increased significantly after immunization with pig cells. In contrast, immunization had little effect on alphaGal-reactive antibody levels in DKO mice. Similarly, pretreatment of GT-/- mice with a blocking antibody to CD21 and CD35 inhibited production of alphaGal-reactive antibodies after immunization. However, DKO mice were able to make alphaGal-specific antibodies after secondary immunization. Thus, Cr2 loci-encoded receptors seem to be directly involved in the production of primary alphaGal-reactive antibodies.