The aromatic retinoids etretinate and acitretin are widely used in the systemic treatment of severe psoriasis. The purpose of the present investigation was to further elucidate the mode of action of acitretin on abnormal keratinization and epidermal hyperproliferation in an in vivo model. Studies on the interference of acitretin with epidermal hyperproliferation and abnormal keratinization in psoriatic plaques are difficult to interpret, as acitretin-induced changes might be due to direct effects of acitretin or be the indirect effect of retinoid-induced modulation of cutaneous inflammation. Using an immunohistochemical assessment, we examined the in vivo effect of systemic acitretin ( > 35 mg daily) on the expression of filaggrin, involucrin, and on the recruitment of cycling epidermal cells, in the tape-stripped uninvolved skin of psoriatic patients, a model which provides the opportunity to study epidermal regeneration in the absence of significant accumulation of T-lymphocytes. During acitretin therapy and 3 weeks after withdrawal of acitretin, we took biopsies from uninvolved skin following tape-stripping in 6 patients with psoriasis. Six patients with psoriasis who had never used acitretin served as controls. We did not observe a Koebner response in our patients after tape stripping. Filaggrin expression was decreased, while the recruitment of cycling epidermal cells and the involucrin expression were increased in the biopsies taken from patients who did not use acitretin. During acitretin treatment, however, the filaggrin expression was similar, whereas the Ki-67 positive nuclei and the involucrin expression showed a statistically significant decrease compared to those parameters in the patients who did not use acitretin. Our findings indicate that epidermal hyperproliferation and abnormal keratinization are modulated directly by acitretin.