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Selective cyclo-oxygenase-2 (COX-2) inhibitors are nonsteroidal antiinflammatory drugs used in the management of inflammatory diseases. We demonstrate here that inhibition of the COX-2 enzyme impairs adipocyte differentiation. The inhibition of adipogenesis occurs in the early clonal expansion phase. In particular, COX-2 inhibition limits cell cycle reentry required before terminal adipocyte differentiation. This inhibition of adipogenesis is independent of the production of the peroxisome proliferator activated receptor γ ligand prostaglandin J2, but dependent on the production of proliferative prostaglandins, such as prostaglandin E2.Modulation of the activity of the COX-2 enzyme via COX-2 selective inhibitors might open up new perspectives in the control of obesity and related metabolic diseases.