Pseudoepitheliomatous hyperplasia has occasionally been reported in cutaneous T-cell lymphoma (CTCL). This association raises the question of the relationship between epidermal hyperplasia and the lymphomatous infiltrate. Because epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) have been demonstrated to be involved in epidermal proliferation through binding to EGF receptor (EGFr), we tested the hypothesis that these cytokines could be secreted by lymphomatous cells, and induce the overlying pseudoepitheliomatous hyperplasia. The purposes of this study were: (i) to describe the clinical and immunohistological features of pseudoepitheliomatous hyperplasia; (ii) to determine its frequency in a large series of CTCLs; and (iii) to evaluate the expression of EGF, TGF-alpha and EGFr in CTCL with or without pseudoepitheliomatous hyperplasia. Eleven cases of CTCL with pseudoepitheliomatous hyperplasia were collected from a series of 353 cases of cutaneous lymphoma registered from 1990 to 1996. They consisted of eight of 28 (28.5%) CD30+ large T-cell lymphomas and three of 148 (2%) cases of mycosis fungoides. Epidermal expression of EGF, EGFr and TGF-alpha was stronger in CTCL than in control normal human skin. Lymphomatous T cells expressed EGF and TGF-alpha whereas no expression of these cytokines could be detected in cutaneous and nodal B-cell lymphomas, nor in a normal lymph node. In addition, epidermal expression of EGFr was stronger in CTCL with pseudoepitheliomatous hyperplasia than in control cases of CTCL without pseudoepitheliomatous hyperplasia, suggesting that these cytokines, in association with other factors, are probably involved in the epidermal hyperplasia observed in some cases of CTCL.