The effects of kappa-casein (CN) and beta-lactoglobulin (LG) genotypes on milk protein concentration and composition were estimated for the US Holstein-Friesian population using a single-trait, mixed, linear animal model on 592 individual milk samples from 233 cows. Both milk protein genotypes had no statistically significant effect on the total milk protein concentration; however, substitution of the kappa-CN A allele additively increased the proportion of kappa-CN, and substitution of the beta-LG B allele additively increased the proportion of beta-LCT in total milk protein. In response, proportions of the other milk proteins, mainly alpha(S1)-CN, were decreased. For proportions of alpha(S1)-CN, kappa-CN, and beta-LG in total milk protein, kappa-CN and beta-LG genotypes explain more than 50 and 25% of the heritability and repeatability estimates, respectively. We concluded that kappa-CN and beta-LG genotypes affect the phenotypic and genetic variation of milk protein composition but do not significantly affect milk protein concentration. A possible explanation for our conclusion is that altered gene sequences in the promoter region of kappa-CN B and beta-LG A, linked closely to the respective genotypes, favor the transcription or translation of their own protein at the expense of the synthesis of other milk proteins, in particular of alpha(S1)-CN.