Biopsy specimens were repeatedly excised from 10 patients with minor and major recurrent aphthous ulcers (RAS). All lesions represented premonitory stages of RAS. The histological and enzyme histochemical investigations were indicative of an early degeneration of individual, suprabasal epithelial cells. The metabolically negative, vacuolated cells were surrounded by cells with normal enzyme activity. No inflammatory reactions were recorded in the connective tissue at this stage. At more advanced stages of the disease the distribution of vacuolated cells within the oral epithelium increased and at the same time an inflammatory reaction in the connective tissue appeared. The vacuolated cells seemed to coalesce and form minor, intraepithelial vesicles. The findings of early intraepithelial degeneration of individual cells in stratum spinosum are compatible with both a viral and an immunological etiology of RAS.