Background: Preeclampsia is a serious human pregnancy disorder that is characterized by widespread maternal endothelial dysfunction and exaggerated inflammation. To date, the etiology of this disease is not well understood. Podocalyxin is a major transmembrane glycoprotein of kidney glomerular podocytes. Investigation of podocalyxin in preeclampsia has thus been limited to urine in association with kidney damage. However, podocalyxin is also expressed in endothelial cells of other organs. In this study we investigated whether podocalyxin is detectable in pregnant serum and whether the levels are altered in preeclampsia. Methods: Podocalyxin was determined by ELISA in sera collected from normal pregnancy across gestation (n=44), and from preeclamptic pregnancies at diagnosis (n=34) with gestation-age-matched controls (n=68). Immunohistochemistry examined podocalyxin in placentas, and in 32 human tissues on a tissue array. Podocalyxin was also examined by ELISA and Western blotting in human umbilical vein endothelial cells (HUVECs) following treatment with pro-inflammatory cytokine IL-6 which is known to be elevated in preeclampsia. Results: Podocalyxin was detected in serum of normal pregnancy, with levels increasing progressively with advancing gestation. Podocalyxin serum levels were significantly elevated in preeclampsia, especially the early-onset subtype. Within the placenta, blood vessels but not trophoblasts expressed podocalyxin, and preeclampsia didn’t differ from controls. Endothelial cells in all 32 human organs examined, as well as HUVECs, expressed podocalyxin. When HUVECs were treated with IL-6, podocalyxinlevels increased in the conditioned media but decreased in the lysates. Conclusion: Podocalyxin likely derived from maternal endothelial cells is present in pregnant serum and significantly increased in early-onset preeclampsia. Podocalyxin release in HUVECs was stimulated by IL-6. These data collectively suggest that serum podocalyxin increase observed in early-onset preeclampsia likely reflects endothelial cell injury/dysfunction and may serve as a novel biomarker of the disease.