Cigarette smoking (CS) has been strongly linked to several health conditions including heart disease, lung cancer, and other respiratory and circulatory ailments. Deleterious effects of cigarette smoking on skin have also been well documented, but unlike effects on other organs, damage does not depend upon inhalation. The upper layer of the skin, the stratum corneum (rich in cholesterol fatty acids and ceramide), is very susceptible to damage induced by exposure to environmental stressors that can modify its lipid composition and thereby affect its function of protecting skin from dehydration. Scavenger receptor B1 (SR-B1) is involved in the uptake of cholesterol in several tissues including skin. We previously demonstrated that CS exposure induces formation of aldehyde (HNE) adducts that decrease SR-B1 expression. As topical resveratrol, a well-known polyphenolic stilbene, has been demonstrated to show benefits against skin disorders, we investigated its possible role as a protective agent against CS-induced reduction of SR-B1 expression in cutaneous tissue. In this study, we demonstrate that resveratrol at doses ranging from 0.5 to 10 μM is not toxic and is able to increase SR-B1 protein levels in a dose-dependent manner in human keratinocytes. Moreover, when the cells that were pretreated with various doses of resveratrol were exposed to CS, the loss of SR-B1 was prevented in a dose-dependent manner. In addition, in keratinocytes, resveratrol was also able to prevent an increase in HNE-protein adducts induced by CS. In particular resveratrol was able to prevent HNE-SR-B1 adduct formation. Thus, resveratrol seems to be a natural compound that could provide skin with a defense against exogenous stressors by protecting the essential cholesterol receptor, SR-B1.