Celecoxib is a potent nonsteroid anti-inflammatory drug (NSAID) that has demonstrated great promise in cancer chemoprevention and treatment. The goal of this study was to determine the inhibitory effect and mechanism of celecoxib on Lewis lung carcinoma. The effect of celecoxib on viability of Lewis lung carcinoma cells was assessed with methyl thiazolyl tetrazolium (MTT) assay. Apoptosis and the mitochondrial membrane potential were detected by flow cytometric assay. The protein expression of cytosolic phospholipase A(2) (cPLA(2)), cyclooxygenase-2 (COX-2), and peroxisome proliferator-activated receptor gamma (PPARγ) were determined by Western blot analysis. The concentrations of arachidonic acid (AA) and prostaglandin E(2) (PGE(2)) in culture supernatants were measured by the methods of RP-HPLC and PGE(2)-specific ELISA, respectively. Celecoxib inhibited the proliferation of Lewis lung carcinoma and induced apoptosis in a dose-dependent manner by breakdown of mitochondrial membrane potential. The protein expressions of cPLA(2) and PPARγ were upregulated, but COX-2 protein expression was downregulated in the Lewis lung carcinoma cells exposed to celecoxib. The amount of AA was increased and PGE(2) was decreased in the culture supernatant, respectively. The ratio of AA to PGE(2) was increased in a dose-dependent manner. The major findings in this study are that celecoxib could inhibit the viability of Lewis lung carcinoma cells by interference of the AA pathway and upregulation of PPARγ simultaneously, which are novel and important since the molecular mechanisms of celecoxib underlying the anti-neoplastic effects remain unclear.