The effects of daily topical application onto guinea pig ears of a therapeutic concentration of all trans-retinoic acid (RA) on epidermal thickness and dermal collagen and glycosaminoglycan (GAG) biosynthesis rates were studied during a 40-day period. Clinically, the RA-treated skin became erythematous and scaly beginning at 5-6 days, conditions which persisted throughout the experiment. The epidermis became thickened and hyperplastic with marked psoriasi-form histologic features, and the phenomenon was dependent on RA concentration. The initial hyperplasia resulted from a transient 4-fold increase in epidermal basal cell replication during the first 3-4 days, as shown by the rise and fall of [3H]thymidine labeling index which preceded the hyperplasia. The extent of epidermal hyperplasia as measured by epidermal thickness was not constant throughout the 40-day treatment period, but exhibited maxima on days 11, 25, and 36. These maxima were followed by periods of decreased thickness, although the minima were always greater than the untreated controls. Retinoic acid induced similar temporal cycles in GAG and collagen biosynthesis rates, but the collagen cycles occurred at different times with maxima on days 6, 20, and 34. After 8 weeks' treatment, the blood flow rates in the ear microcirculation (laser Doppler photometry) were increased 81% above that of the water-treated controls. The demonstration of these RA-induced cyclic changes in epidermal hyperplasia and dermal fibroblast biosynthetic activities have revealed the presence of control mechanisms in these tissues which normally operate to maintain tissue homeostasis.