Cyclooxygenase-2 (COX-2) is expressed within neovascular structures that support many human cancers. Inhibition of COX-2 by celecoxib delays tumor growth and metastasis in xenograft tumor models as well as suppresses basic fibroblast growth factor 2 (FGF-2)-induced neovascularization of the rodent cornea. The present studies were undertaken to evaluate possible mechanisms of the antiangiogenic and anticancer effects of celecoxib. Prostaglandin E₂ (PGE₂) and thromboxane B₂ (TXB₂) were increased in rat corneas implanted with slow-release pellets containing FGF-2 (338.6 ng of PGE₂/g and 17.53 ng of TXB₂/g) compared with normal rat corneas (63.1 ng of PGE₂/g and 2.0 ng of TXB₂/g). Celecoxib at 30 mg/kg/day p.o. inhibited angiogenesis (78.6%) and prostaglandin production by 78% for PGE₂ (72.65 ng/g) and 68% for TXB₂ (5.55 ng/g). Decreased prostaglandin production in corneas was associated with a 2.5-fold cellular increase in apoptosis and a 65% decrease in proliferation. Similar reductions in proliferation were observed in neovascular stroma (65–70%) of celecoxib-treated (dietary 160 ppm/day) xenograft tumors as well as in tumor cells (50–75%). Apoptosis was also increased in the tumor cells (2.2–3.0-fold) in response to celecoxib. Thus, the antitumor activity of celecoxib may be attributable, at least in part, to a direct effect on host stromal elements, such as the angiogenic vasculature.