Human epidermal keratins from many different individuals were identified and compared by both high-resolution 1- and 2-dimensional gel electrophoresis and immunoblotting. While the polypeptide patterns obtained for keratin-enriched cytoskeletal preparations could be considered typical of normal interfollicular epidermis, they also disclosed variations, among the individuals, concerning some of the constituent protein subunits. Three sets of interindividually varying keratins could be distinguished owing to their distinct, though small, differences in electrophoretic mobility on sodium dodecyl sulfate-polyacrylamide gels and their similar or identical charge characteristics upon nonequilibrium pH gradient electrophoresis: the basic keratins 1a and 1b as well as 5a and 5b and the acidic keratins 10a and 10b. Of each set either a doublet, showing a marked 1:1 ratio of polypeptides, or the one or the other variant protein was detected together with keratin 14, which did not display any variation in a series of 148 individual tissue samples tested. Thus, the keratin composition of human epidermis could be summarized in the formula: (1a v 1b) + (5a v 5b) + (10a v 10b) + 14. The systematic appearance of the variants suggested that each protein within a set is the product of an independent allele. In support of this hypothesis we have found that the same variant is expressed in other epithelia of a given individual. Moreover, the frequency of any of the keratins in our sampling concurred with the frequency predicted by the Hardy-Weinberg relation for the distribution of alleles in a population, as did the frequency distribution of particular keratin patterns.