The basic keratin pattern of mammalian epidermis consists of the basal keratin pair K5/K14 and the differentiation-specific keratin pair K1/K10. Distinct skin sites of the adult mouse, i.e., ear, sole of the foot, and interscale regions of tail skin, express an additional, type II 70-kilodalton (kDa) keratin without a defined new type I partner in suprabasal epidermal cells. Until now, the question whether this large keratin is specific for the mouse (or related small rodents) or whether orthologous keratins exist in other species has not yet been answered. In the present study, we have determined the full-length amino acid sequence of the 70-kDa keratin. The keratin comprises 707 amino acid residues and has a calculated molecular weight of 70,976.70 Da. From the structural point of view, the 70-kDa keratin is remarkable in that more than half of both the V1 and V2 subdomains of its non alpha-helical head and tail portions consist of different glycine-rich peptide motifs that are configured consecutively at least two times and as much as seven times in tandem. By means of sequence comparisons and phylogenetic investigations, we show that the 70-kDa keratin represents the murine ortholog of the human 65-kDa keratin K2e, whose nature as a genuine keratin has recently been demonstrated. The unusually large size difference of 5 kDa between MK2e and HK2e is due mainly to a different duplication rate of the glycine-rich peptide motifs in the respective V subdomains of the orthologous keratins. We discuss the properties of these highly specialized keratins, which in both species define locally restricted epidermal keratin phenotypes, and compare them with other orthologous keratins that belong to the basic epidermal keratin pattern.