Background: The mature psoriatic lesion does not necessarily demonstrate changes relevant to early phases of the lesion. Objective: In a model for relapsing psoriasis we examined the epidermal phenotype by means of a panel of immunohistochemical parameters: keratins 14 and 16, epidermal growth factor receptor (EGFR), Ki-67 antigen, and Tdt-mediated Unscheduled Nick End Labeling to detect apoptosis. Methods: In 9 patients, we cleared psoriatic plaques by topical treatment with clobetasol-17-propionate under hydrocolloid occlusion. Relapse (defined as a clinical sum score ≥ 6) was awaited. Biopsy specimens of the psoriatic lesion, the cleared skin, the relapsed plaque, and its clinically normal margin were assessed. Results: Psoriasis recurred after 19 ± 6 weeks (mean ± SEM). During treatment all parameters improved considerably; however, the number of apoptotic cells was not affected.Ki-67 values decreased well below the normal range. At initial relapse, the symptomless skin adjacent to the relapsing lesion (margin) showed a marked expression of keratin 16 and EGFR. Ki-67 expression was increasing in the margin but was below values of the mature lesion. The localization of cycling cells in the first suprabasal layers was a remarkable feature. Keratin 14 expression was increased in the recurrent lesion itself, but not in the symptomless margin. Conclusion: Keratin 16 and EGFR expression are early phenomena in the evolution of the lesion, and they anticipate epidermal proliferation. The expression of keratin 14 follows overt epidermal hyperproliferation. The present observation in incipient psoriasis lends support to the hypothesis that the basal cell compartment does not have a primary involvement in the initiation of epidermal abnormalities in psoriasis, but that a coordinated sequence of events involving proliferation and differentiation markers in the first suprabasal layers of the epidermis could be the key to the pathogenesis of this puzzling disease. (J Am Acad Dermatol 1999;40:901-9.)