Introduction: Vascular endothelial growth factor (VEGF) is a potent mediator of angiogenesis. VEGF-A gene produces 6 proteins of varying length from 121-206 amino acids, with VEGF165 as the dominant form in human placenta. Recently a VEGF165b has been identified that competitively inhibits VEGF165 action by binding to VEGF receptor KDR, and inhibit receptor phosphorylation and downstream intracellular signaling. Objective: In this study, we have examined the placental expression of VEGF165b in normal women throughout gestation. Methods: In an IRB approved study, placentas were obtained from normal pregnant women who underwent elective abortion or term delivery. Tissues were collected and dissected in saline to identify chorionic villi without associated decidua. Cytotrophoblast VEGF165b expression was assayed using ELISA kit DY3045 (R&D Systems, Minneapolis, MN). Non-parametric tests considered p<0.05 as significant. Results: VEGF165b protein was detected throughout gestation. VEGF165b protein expression differed significantly among the trimester groups (p<0.0001), with median VEGF165b protein expression peaking in the second trimester. A significant positive correlation between VEGF165b protein expression and gestational age (GA) in days was noted in the first trimester (rho=0.327, p<0.001) and a negative but insignificant correlation thereafter. Conclusions: Our findings of VEGF165b in all 231 placentas analyzed suggest that VEGF165b may have a regulatory role in human pregnancy. VEGF165 is overexpressed in many cancers while VEGF165b is down-regulated in renal cell carcinoma. We speculate that VEGF165b protein expression in placental tissues could be a physiological phenomenon during placental development to restrain overexpression of VEGF that could lead to pregnancy complications.