Embryo implantation requires extensive angiogenesis at the maternal‐fetal interface. Hyperglycosylated human chorionic gonadotropin (hCG‐H), a trophoblast invasive signal produced by extravillous cytotrophoblasts and by choriocarcinoma, was evaluated for its angiogenic role. hCG‐H was purified by HPLC from choriocarcinoma supernatant, and the glycosylation pattern was determined by 2D gel analysis. Angiogenesis models used were aortic ring assay with wild‐type and LHCGR‐knockout mice, endothelial and mural cell proliferation, and migration assays. The TGF‐β signaling pathway was studied by coimmunoprecipitation, competitive binding, TGF‐β reporter gene assays, and Smad immunoblotting. hCG‐H displayed a potent angiogenic effect [3.2‐fold increase of number of vessel intersections in wild‐type aortic rings (11.406 to 36.964)]. hCG‐H‐induced angiostimulation was independent of the classic hCG signaling pathway since it persisted in LHCGR‐knockout mice [4.73‐fold increase of number of vessel intersections (10.826 to 51.288)]. Using TGF‐β signaling inhibitors, Tβ‐RII was identified as the hCG‐H receptor responsible for its angiogenic switch. hCG‐H exposure enhanced phosphorylation of Smad 2 in endothelial and mural cells and genomic activation of Smad‐responsive elements. Interaction between hCG‐H and Tβ‐RII was demonstrated by coimmunoprecipitation and binding competition with ¹²⁵I‐TGF‐β. This new paracrine interaction between trophoblast and endothelial cells through the hCG‐H and the TGF‐β receptor complex plays a key role in angiogenesis associated with placental development and tumorigenesis.—Berndt, S., Blacher, S., Munaut, C., Detilleux, J., Perrier d'Hauterive, S., Huhtaniemi, I., Evain‐Brion, D., No�l, A., Fournier, T., Foidart, J.‐M. Hyperglycosylated human chorionic gonadotropin stimulates angiogenesis through TGF‐β receptor activation. FASEB J. 27, 1309–1321 (2013). www.fasebj.org