© 2017 The American Society of Photobiology Naproxen possesses anti-proliferative and pro-apoptotic effects besides its known anti-inflammatory functions. Here, we demonstrate the anticancer effects of naproxen against UVB-induced basal cell carcinoma (BCCs) and squamous cell carcinoma (SCCs) in a highly susceptible murine model of UVB carcinogenesis. Naproxen significantly inhibited UVB-induced BCCs and SCCs in this model. Tumor number and volume were significantly decreased (P < 0.005 and P < 0.05, respectively). Inhibition in UVB-induced SCCs and BCCs was 77% and 86%, respectively, which was associated with reduced PCNA and cyclin D1 and increased apoptosis. As expected, inflammation-related iNOS, COX-2 and nuclear NFκBp65 were also diminished by naproxen treatment. Residual tumors excised from naproxen-treated animal were less invasive and showed reduced expression of epithelial-mesenchymal transition (EMT) markers N-cadherin, Vimentin, Snail and Twist with increased expression of E-cadherin. In BCC and SCC cells, naproxen-induced apoptosis and activated unfolded protein response (UPR) signaling with increased expression of ATF4, p-eIF2α and CHOP. Employing iRNA-based approaches, we found that naproxen-induced apoptosis was regulated by CHOP as sensitivity of these cutaneous neoplastic cells for apoptosis was significantly diminished by ablating CHOP. In summary, these data show that naproxen is a potent inhibitor of UVB-induced skin carcinogenesis. ER stress pathway protein CHOP may play an important role in inducing apoptosis in cancer cells.