Daily topical treatment with all-trans-retinoic acid (t-RA; 0.1% t-RA solution or 0.05% t-RA cream) was compared with its vehicle with regard to improvement of intrinsically aged skin of hairless descendants of Mexican hairless dogs. After 1 mo of treatment with 0.1% t-RA solution, improvements were noted in skin texture, wrinkling, and pigmentation. Treatment with 0.05% t-RA cream caused an intense adverse effect, retinoid dermatitis. Histologically, 0.1% t-RA solution induced restoration of the skin structure of hairless dogs, resulting in an apparent increase in compaction of the stratum corneum and the epidermal thickness. The epidermis became hyperplastic with definite development of the stratum granulosum. The border between the epidermis and dermis became wavy, and dermal papillae were reconstituted. The 0.1% t-RA solution caused a remarkable decrease in melanin granules. In the dermis, the number of small vessels increased and vasodilation was seen. In sites treated with 0.05% t-RA cream, the stratum corneum became involved in dyskeratotic changes. There was a significantly greater increase in epidermal and granular layer thickness. Necrotic and edematous changes were found in the epidermis, and severe inflammatory reactions were also observed in the dermis. In the t-RA-untreated sites, the structure of the aged skin remained histologically unimproved during the study. The results suggest that hairless dogs are useful laboratory animals for evaluating the effectiveness and side effects of t-RA agents.