It is generally recognized that epithelial cytokeratins (CKs) are expressed in tissue-specific patterns and reflect differentiation, functional specialization, and pathological alterations of the cells. Differential epithelial cell types can thus be distinguished from each other by their selective expression of particular sets of CKs. To determine the characteristics of metaplastic and hyperplastic changes of alveolar-lining epithelial cells in the lungs of idiopathic pulmonary fibrosis (IPF), the expression of individual CKs was studied immunohistochemically using monospecific anti-CK monoclonal antibodies (anti-CKs 7, 8, 10, 13, 14, 16, 17, 18, 19). Biopsy specimens from 17 patients with IPF and normal lung tissues (NL) from seven patients with lung cancer were studied. In the IPF specimens, several kinds of altered epithelial cells were observed, which showed characteristic changes in CK expression compared with NL, especially CKs 8, 14, and 17. Hyperplastic type II cells expressed increased CKs 7, 8, and 19, but not CK 17; flattened or stratified squamous metaplastic cells expressed increased CKs 17 and 14, co-expressed with CKs 7, 8, and 19; bronchiolar metaplastic cells expressed increased CKs 7, 8, and 19, co-expressed with CKs 14 and 17; cuboidal metaplastic cells expressed increased CKs 7, 8, 17, and 19. The quantification of individual CKs in the tissues by enzyme-linked immunosorbent assay revealed increased expression of CKs 8, 14, and 17 in IPF lung tissues compared with NL. These results were consistent with the immunohistochemical observations. The hyperplastic and bronchiolar metaplastic phenotypes were characterized by their increased expression of simple CKs without CK alteration. The squamous metaplastic phenotype showed CK alterations, with the appearance of CKs 17 and 14. Epithelial cells are thus altered not only in shape, but possibly also in differentiation and function, with potential implications for the pathogenesis of IPF.