Standard chemotherapeutic agents used for the treatment of pre-cancerous skin lesions and non-melanoma skin cancers are not completely effective. Several studies have suggested that repeated inflammatory sunburn reactions, which include the induction of cyclooxygenase-2 (COX-2) and the subsequent production of prostaglandins, play a role in skin cancer development. COX-2 inhibition has been demonstrated to be a potent means of preventing skin cancer development in mice; however, COX-2 inhibitors alone are not effective as chemotherapeutic agents. Data in a variety of cancer types suggest greater efficacy in treating tumors with combination chemotherapies. Therefore, we hypothesized that a combination of the chemotherapeutic agent 5-fluorouracil (5-FU) and the COX-2 inhibitor and anti-inflammatory drug celecoxib would act synergistically to regress tumors in a murine model of ultraviolet light B- (UVB-) induced carcinogenesis. We found that topical treatment with 5-FU and celecoxib together was up to 70% more effective in reducing the number of UVB-induced skin tumors than 5-FU treatment alone. Our data suggest that more effective chemotherapy regimens can be developed to treat the millions of pre-cancerous and cancerous skin lesions that arise every year, which could ultimately lead to a significant reduction in costs and cosmetic defects (scarring) associated with surgical interventions.