Heteroduplex analysis shows that the transferrin receptor gene contains at least 19 distinct coding sequences distributed over 31 kb of genomic DNA. The nucleotide sequence of these coding regions has been determined from a cDNA clone. The sequence contains a single complete open reading frame of 2280 bases which specifies a 760 residue polypeptide with a molecular weight of 85K daltons. The deduced amino acid sequence of the receptor shows that it does not contain an N-terminal hydrophobic signal peptide. We have found a single region of sufficient length and hydrophobicity to span the membrane, located 61 amino acids from the N-terminus. This leads to the prediction that the receptor is oriented in the membrane with a cytoplasmic N-terminus and an extracellular C-terminus. The receptor has no significant homology with transferrin, or with any receptor for which a sequence is available.