Polyphenols are the abundant micronutrient in our diet and attention has been given to them for the prevention of degenerative diseases. Since over production of ROS and proinflammatory cytokine are often act as the triggers for the promotion stage of carcinogenesis by transcriptional up-regulation of nuclear factor-κB (NF-κB) and cycloxygenage-2 (COX-2). We investigated the protective effects of caffeic acid (CA) on 12-O-tetradecanoyl-phorbol-13-acetate (TPA) induced oxidative and inflammatory responses, expression of NF-κB and COX-2 in mouse skin. Animals were given pre-treatment of CA at two different doses 10μmol (D1) and 20μmol (D2)/0.2ml of acetone 30min prior to each TPA (10nmol/0.2ml of acetone) application. Our results show that CA significantly inhibit the TPA induced lipid peroxidation (LPO), inflammatory responses, tumor necrosis factor alpha (TNF-α) release and also found to up regulate GSH content and the activity of different antioxidant enzymes. Further, CA was found to inhibit the TPA induced expression of NF-κB and COX-2. Thus, our results suggest that CA attenuates TPA induced tumor promotional triggers possibly by inhibition of oxidative and inflammatory responses thereby diminishing the expression of NF-κB and COX-2. Copyright © 2011 Elsevier Ltd. All rights reserved.