Five patients with widespread plaque-type psoriasis were treated continuously with clobetasol under occlusion. Clinical healing was seen after 6–10 days of treatment. All plaques treated in this way clinically relapsed approximately 12 days later. During the period of remission, sequential biopsies were taken and prepared for light and electron microscopy. Histologically, the earliest indications of relapse were endothelial alterations (swelling, intercellular widening) followed by the appearance of mast cells around the postcapillary venules; these mast cells showed signs of degranulation. Hours later, activated macrophages showing pericellular edema were present, and these migrated into the epidermis soon after. Associated with the presence of macrophages, there was a complete loss of desmosome-tonofilament complexes. Later, lymphocytes and neutrophils were seen. Under these experimental conditions, the psoriatic-tissue alterations appear to have been initiated by degranulating mast cells as well as by macrophages which later invaded the epidermis.