Prostaglandin levels vary during pregnancy, mostly under the control of the inducible enzyme cyclooxygenase-2 (COX-2). The expression of COX-2 has been associated with ischemic events in the heart and brain, but its direct effect on human placental perfusion has not been previously examined. The purpose of this study was to investigate whether a functional polymorphism in the COX-2 gene that controls enzyme expression levels is associated with placental histopathologic lesions. Maternal and neonatal DNA from twin gestations were analyzed by a polymerase chain reaction-based assay for a single G to C nucleotide polymorphism at position -765 in the COX-2 gene promoter. Placental histopathology was evaluated in 6 major categories: meconium, malperfusion, inflammation, umbilical cord problems, villitis, and thrombosis. There was no significant association between placental histopathologic findings and polymorphisms of the COX-2 gene in the mother. In the fetus, carriage of the COX-2 C allele, which is correlated with decreased COX-2 gene expression, was negatively associated with lesions of placental ischemia/malperfusion (P = 0.02). Placental ischemic lesions were positively associated with intrauterine growth restriction (IUGR; P < 0.001). No other group of histopathologic lesions was associated with fetal polymorphisms in the COX-2 gene or with IUGR. Thus, a fetal polymorphism in the COX-2 gene influences the occurrence of placental malperfusion and ischemia, which may be of sufficient severity to promote or allow the development of IUGR.