In many mammalian species antibodies transmitted from the mother provide humoral immunity to the young. Maternal IgG from milk is transported across the intestinal epithelium of neonatal rats by an Fc receptor (FcRn) that comprises an alpha-chain similar to the class I Ag of the MHC and beta 2-microglobulin. Suckling mice also acquire antibodies by uptake from the gut. We made a neonatal mouse intestinal cDNA library and screened it with a probe encoding rat FcRn alpha-chain. The nucleotide and predicted amino acid sequences of the two positive clones were very similar to those of rat FcRn. Comparison of the FcRn domains to various MHC class I and CD1 molecules suggests a divergence of FcRn from MHC early in the mammalian lineage. We expressed one of these cDNA in mouse 3T3 fibroblasts. Cells that expressed the cDNA product bound the Fc fragment of IgG with the same pH dependence as neonatal rat intestinal epithelium. We detected RNA that hybridize with the mouse cDNA only in neonatal small intestine and fetal yolk sac, two tissues involved in IgG transport. These data show that the mouse cDNA code for FcRn alpha-chain. The mouse FcRn alpha-chain is similar in sequence to the class I MHC Ag, encoded on chromosome 17 in the mouse. However, we find that the mouse FcRn gene lies outside the MHC, on chromosome 7.