The underlying causes of epithelial ovarian cancer (EOC) are unclear, and treatment options for patients with advanced disease are limited. There is evidence that the use of nonsteroidal anti-inflammatory drugs is associated with decreased risk of developing EOC. Nonsteroidal anti-inflammatory drugs inhibit cyclooxygenase (COX)-1 and COX-2, which catalyze prostaglandin biosynthesis. We previously showed that mouse and human EOCs have increased levels of COX-1, but not COX-2, and a COX-1-selective inhibitor, SC-560, attenuates prostaglandin production and tumor growth. However, the downstream targets of COX-1 signaling in EOC are not yet known. To address this question, we evaluated peroxisome proliferator-activated receptor δ (PPARδ) expression and function in EOC. We found that EOC cells express high levels of PPARδ, and neutralizing PPARδ function reduces tumor growth in vivo. More interestingly, aspirin, a nonsteroidal anti-inflammatory drug that preferentially inhibits COX-1, compromises PPARδ function and cell growth by inhibiting extracellular signal-regulated kinases 1/2, members of the mitogen-activated protein kinase family. Our study, for the first time, shows that whereas PPARD can be a target of COX-1, extracellular signal-regulated kinase is a potential target of PPARδ. The ability of aspirin to inhibit EOC growth in vivo is an exciting finding because of its low cost, lack of cardiovascular side effects, and availability.