Cyclooxygenase-2 (COX-2), an enzyme that catalyzes the synthesis of prostaglandins, is made inducible by various stimuli such as inflammation. Although COX-2 is commonly overexpressed in a variety of premalignant and malignant conditions including oral leukoplakia and squamous cell carcinoma, relatively little research has compared the effects of various COX-2 inhibitors (celecoxib, NS-398, nimesulide and meloxicam). Therefore, we investigated the effects of four different selective COX-2 inhibitors on the growth of KB cells, derived from oral squamous cell carcinoma (OSCC) and its mechanisms. Celecoxib and NS-398 strongly suppressed the proliferation of KB cells at 10-100 microM, whereas nimesulide and meloxicam are less potent proliferation inhibitors. Only celecoxib induced apoptosis of the KB cells, as detected on the basis of DNA fragmentation, caspase-3/7 activation and cleaved poly(ADP-ribose) polymerase (PARP) fragmentation. All four COX-2 inhibitors increased COX-2 protein expression but suppressed prostaglandin (PG) E2 production in the KB cells, suggesting that the pro-apoptotic effect of celecoxib was unrelated to the inhibition of COX-2. Mechanistically, a high level of p53 protein and a low level of multidrug-resistant protein 1 (MRP1) and breast cancer resistant protein (BCRP) mRNA in KB cells with celecoxib may explain the differential effect of these selective COX-2 inhibitors in KB cells. Taken together, celecoxib is a good therapeutic candidate for treating OSCC through the suppression of cell proliferation and the induction of apoptosis in a COX-2 independent manner.