Two electrophoretic variants for each of the human keratins K4 and K5 that are expressed in squamous nonkeratinizing epithelia lining the upper digestive tract could be distinguished on SDS-PAGE. Based on a sampling size of 1,299 unrelated individuals, calculation of allele frequencies showed the alleles to be in Hardy-Weinberg equilibrium. The genetic basis of this variation was confirmed by both quantitative gene dosage dependence and the transmission of the variants as Mendelian traits in two families. Thus the human keratin genes K4 and K5 are polymorphic, and each presents with two codominant alleles (a and b).