In this review, we summarize the results of a number of our recent in vitro and in vivo experiments demonstrating that, in addition to the immunoregulatory functions, soluble HLA-G molecules also affect endothelial cell activity. We have found that soluble HLA-G1 (also designated HLA-G5) inhibits endothelial cell proliferation, migration and tubule formation, and this occurred through binding to the CD160 receptor and via an apoptotic pathway. Moreover, we have demonstrated that soluble HLA-G1 blocks in vivo rabbit corneal neoangiogenesis. Although it cannot be excluded that other soluble HLA class I molecules may have similar effects, as soluble forms of HLA-G are being produced by trophoblast cells at the maternal-fetal interface during early gestation, we discuss how such anti-angiogenic properties of soluble HLA-G1 may locally influence uterine vascular remodeling.