The present study was designed to explore if *etinaldehyde, a natural metabolite of vitamin A, has any biologic activity and is tolerated by human skin. Biologic activity was shown by the induction of cellular retinoic acid-binding protein type 2 (CRABP 2) mRNA and protein; the rank order for CRABP-2 increase was retinoic acid > retinaldehyde > 9 cis retinoic acid > retinol > beta carotene. In volunteers treated 1-3 months with 0.5, 0.1, and 0.05% retinaldehyde, there was a dose-dependent and significant increase in epidermal thickness, keratin 14 immunoreactivity, and Ki67-positive cells. The area of distribution of involucrin, transglutaminase, and filaggrin immunoreactivity was also increased in a dose-dependent manner, and keratin 4 immunoreactivity was induced in the upper epidermis. In pilot clinical tolerance studies, 229 patients received topical retinaldehyde at different concentrations; the 1% preparation was tolerated by up to 70% of the treated subjects; tolerance of the 0.5% preparation was slightly better, whereas both 0.1 and 0.05% preparations applied on facial skin were well tolerated and allowed prolonged use (up to 3 years) in patients with inflammatory dermatoses. These findings indicate that topical retinaldehyde has biologic activity and is well tolerated on human skin.