Loricrin is a glycine-, serine-, and cysteine-rich protein expressed very late in epidermal differentiation in the granular layers of normal human epidermis. Subsequently, loricrin becomes cross-linked by the activity of transglutaminases TGK/E as a major component of the cornified cell envelope by N epsilon-(gamma-glutamyl)lysine isopeptide bonds. In this study, 115 biopsy specimens from patients with various cutaneous diseases with a morphologically altered epidermal differentiation were analyzed with use of immunohistology with antibodies to loricrin and to involucrin. In addition, antibodies to filaggrin were used for ichthyotic lesions. In contrast to involucrin, loricrin expression was consistently down-regulated in agranulotic, parakeratotic keratinization as observed in psoriasis, dermatitis, pityriasis lichenoides, porokeratosis, or precancerous and malignant squamous lesions. High levels of loricrin were found in hypergranulotic and hyperorthokeratotic epidermis as observed in lichen planus, benign papillomas, and pseudocarcinomatous hyperplasia. Eleven biopsy specimens from patients with ichthyosis vulgaris showed a normal staining in the granular layers. Our results demonstrate that loricrin expression is closely linked to an orthokeratotic phenotype of human epidermal keratinization. The different expression patterns of loricrin and involucrin provide further evidence that these proteins are regulated by different mechanisms and serve different functions during terminal epidermal differentiation.