Background/Aim: Cigarette smoke (CS) is a major environmental health threat. The oxidative stress induced by CS on keratinocytes and the possible protective effect of nicotine, its receptor inhibitors, and Pinus halepensis bark extract in relation to known antioxidants were investigated. Materials and Methods: Primary mouse keratinocytes were exposed to cigarette smoke in the presence and absence of Pinus halepensis bark extract (1 μg/ml), rutin (50 μΜ) and ascorbic acid (250 μΜ), nicotine (1 μM) with or without mecamylamine (5 μM) and α-bungarotoxin (0.1 μΜ). Keratinocyte viability and oxidative stress were evaluated by MTT and fluorescence assays. Results: Pinus halepensis bark extract decreased the oxidative stress and increased the viability of keratinocytes, and moreover, these effects were more pronounced compared to the mixture of rutin and Lascorbic acid. Nicotine significantly enhanced the viability potentiation of the beneficial effect induced by Pinus halepensis bark extract. Mecamylamine and α-bungarotoxin showed no specific effect. Conclusion: Pinus halepensis bark extract in combination with nicotine may successfully reverse skin damage induced by cigarette smoke. Cigarette smoke (CS) is a global problem of our society and according to the World Health Organization "the tobacco epidemic is one of the biggest public health threats the world has ever faced, killing more than 8 million people a year" (1). The Lancet Commission on pollution and health characterized CS as more dangerous than AIDS, tuberculosis, and malaria (2). CS is associated with cardiovascular diseases, higher risk of skin diseases, such as squamous cell carcinoma and atopic dermatitis, and is connected with decreased wound healing rate (3-7). The skin is the most important target for the harmful effect of CS pollution. Both solid and gas products of CS contain aniline, N-nitrosodimethylamine, benzopyrenes, acrolein, formaldehyde, N-nitrosopyrrolidine that are considered to be toxic, causing serious oxidative damage (8). CS produces reactive oxygen and nitrogen species oxidizing important biomolecules such as DNA, proteins and lipids leading to tissue injury which is translated to enhanced inflammatory phenomena (9-14). One of the main constituents of CS is nicotine; it is an agonist of acetylcholine and acts on the epidermis via the keratinocyte nicotinic acetylcholine receptors (nAChRs) (15). nAChRs are large (290 kDa) pentameric transmembrane complexes, which are ligand-gated ion channels (LGICs) permeable to Na, K and Ca ions (16, 17). Nicotine activity is doubtful as it has been shown to exert both toxic and beneficial effects; it has been reported as neurotoxic and neuroprotectant (18), toxic to muscles and lung epithelium (19, 20), beneficial in colitis (21), while its potential activity on mitochondria apparently requires further investigation (22). Concerning inflammatory and wound healing processes, the effect of nicotine is considered rather negative, while topical nAchR antagonists have been shown to improve these negativ...