The purpose of this study was to determine the distribution and the expression of vascular endothelial growth factor (VEGF) in human placentas obtained from 22 cases of nonimmunologic hydrops fetalis (NIHF), ranging from 25 to 41 weeks of gestation, as compared with those in 75 normal placentas. The terminal villi were examined immunohistochemically using rabbit anti-human VEGF immunoglobulin G. The expression of VEGF in the terminal villi was assessed by the ratio of the VEGF-positive area to the capillary area. Among the 22 placentas, 18 placentas were hydropic and appeared to be histologically immature, and the other 4 placentas, whose fetuses eventually recovered before their deliveries, were nonhydropic. In both the HF and normal placentas, syncytiotrophoblasts expressed VEGF in the villi throughout gestation. VEGF was also expressed by stromal cells in the terminal villi of normal placentas in only the first trimester, whereas its expression continued until the term of pregnancy in 12 of 18 HF placentas. The ratio of the VEGF-positive area to the capillary area was significantly higher in the terminal villi of all hydropic HF placentas than in those of the normal placentas but was entirely the same in the four nonhydropic placentas as in the normal control placentas. These results suggest that the persistent expression of VEGF by stromal cells in the hydropic villi of NIHF, in addition to the VEGF expression by syncytioptrophoblasts, seems to be a reaction to poor villous vascular development and to participate in the regulatory mechanisms of vascular function including angiogenesis and permeability.