Elafin is a serine proteinase inhibitor highly expressed in psoriatic epidermal keratinocytes, but expressed scarcely, if at all, in normal skin. In addition to the proteinase inhibiting domain, elafin contains multiple transglutaminase substrate domains and has been identified as a constituent of the epidermal cornified cell envelope. It also contains a signal peptide sequence, and previous immunoelectron microscopy studies detected elafin in lamellar granules and also in the intercellular spaces. It has not been explained, however, how and when elafin molecules stored in the granules are cross-linked into the cell envelope. In order to elucidate this issue, we performed pre-embedding and postembedding immunoelectron microscopy of elafin and involucrin, another cell envelope constituent, using psoriatic epidermis. Postembedding double immunoelectron microscopy revealed that elafin was within the secretory (lamellar) granules and released into the intercellular spaces when the cell envelope was not formed. In the cells with involucrin-positive cell envelope, elafin immunolabels were localized diffusely within the cells and also along the cell envelope. Pre-embedding immunoelectron microscopy of purified cell envelope from psoriatic scale samples detected involucrin and elafin colocalizing on the cytoplasmic side of the cell envelope. These findings strongly suggest that elafin-containing granules are disintegrated upon the initiation of cell envelope formation, and that elafin is cross-linked on to the involucrin-positive cell envelope from the inside of keratinocytes. It seems that psoriatic keratinocytes utilize elafin as a major component of the cell envelope, consistent with the previously proposed "precursor availability hypothesis".