Thrombosis of large fetal vessels in the placenta leads to regions of downstream avascular villi (AV). Avascular villi have been associated with adverse outcomes in anecdotal reports, but no controlled study of their significance has been done. We prospectively gathered cases of extensive AV (n = 29) occurring over a 2-year period at the Institute of Pathology at Case Western Reserve University and compared obstetric history, coexistent placental pathology, and neonatal outcome to gestational age-matched controls in a case control study. The diagnosis of extensive AV required one or more of the following characteristics: 2.5% or more of total villous parenchyma affected, foci in multiple sections, or a single lesion measuring 0.25 cm2 or larger. Women with AV placentas had increased rates of intrauterine growth retardation (IUGR), acute and chronic monitoring abnormalities, oligohydramnios, and maternal coagulation disorders. Placentas with AV were more likely to have coexistent chronic villitis, membrane hemosiderin, meconium in all three membrane layers, and villous chorangiosis. Finally, among the subgroup of neonates older than 34 weeks gestation without congenital malformations or coexistent placental pathology (n = 18), we identified significant abnormalities, including major thrombotic events (n = 5), neonatal death (n = 2), umbilical artery pH less than 7.10 (n = 4), platelet count less than 150,000 (n = 4), increased nucleated red blood cell (NRBC) counts (n = 7), and transient hypoglycemia (n = 4). Placental features correlating with clinical abnormalities included percentage of greater than 30% AV, recent platelet and fibrin aggregates, and multifocal disease involving more than one histological section.