Treatment of psoriasis with vitamin D3 analogues is well established in present dermatological practice. One of the clinical signs of the psoriatic plaque that reduces early and markedly during treatment with the vitamin D3 analogue calcipotriol is scaling. Since scaling is the clinical manifestation of disordered epidermal differentiation, early changes in immunohistochemical markers for differentiation (transglutaminase, involucrin and filaggrin) were studied in patients who had been treated with calcipotriol for 4 weeks. Markers for proliferation (Ki-67 antigen) and inflammation (polymorphonuclear leucocytes and T lymphocytes) were also studied and correlated with the differentiation characteristics. Clinically, a major improvement was seen in all patients. A significant decrease in the percentage of transglutaminase-positive cell layers was observed during the first week of treatment. In contrast, an increase in transglutaminase activity in epidermal cell cultures following incubation with calcipotriol has been reported. Involucrin expression was only slightly modulated in vivo. However, a major restoration of the filaggrin-positive cell layer and significant reduction in the recruitment of cycling epidermal cells characterized the epidermal response to calcipotriol treatment. Markers for inflammation (T11-positive cells and elastase-positive cells) were also reduced substantially during the first week of treatment with calcipotriol. From this study it may be concluded that inhibition of epidermal growth and recovery of the filaggrin-positive cell layer are among the in vivo effects of calcipotriol.