Both DNA and RNA disappear from the nucleus during differentiation of granular cells into cornified cells but the fate of nuclear proteins remains unknown. We investigated localization of nuclear proteins in rat epidermis by light and electron microscopic immunoperoxidase techniques. As a probe, three sera that reacted, respectively, with the nucleoplasm, nucleolus, and nuclear envelope of basal cells of rat epidermis were used. In granular cells both the antinucleoplasm serum and antinucleolus serum increased intensity of the nuclear staining, but they reacted also with ribosomes, filaments, and periphery of keratohyalin granules in the cytoplasm. The staining appeared diffusely in cornified cells and identification of nuclear components became impossible. In contrast, the antinuclear envelope serum stained only the nuclear outline in granular cells and continued to stain the nuclear contour in cornified cells of the fourth and fifth proximal cell layers. The antigenic components surrounded amorphous but not filamentous materials in cornified cells. These findings suggest that some nuclear proteins become immunologically indistinguishable from cytoplasmic protein. However, the nuclear envelope protein maintains its localization even after nucleic acids are lost and the nuclear space is detectable in cornified cells by use of autoantibody directed to this protein(s).