The histologic effects of topical tretinoin therapy on photodamaged facial skin were investigated in two 24-week, double-blind, randomized, vehicle-controlled studies involving 533 subjects at eight US centers. Three concentrations of tretinoin (0.05%, 0.01%, and 0.001%) in a new emollient cream were studied. Pretherapy and posttherapy biopsy specimens from the periorbital (crow's foot) area were examined by conventional light microscopy and computerized image analysis. Four significant dose-dependent differences from vehicle were found in the tretinoin groups: increased epidermal thickness, increased granular layer thickness, decreased melanin content, and stratum corneum compaction. There was no significant difference between 0.001% tretinoin and the vehicle, and no obvious dermal changes were detected in any group. The four epidermal changes in tretinoin-treated skin establish the biologic activity of the new emollient cream formulation and may partially account for the clinical improvements in photodamage observed in the same group of subjects.