The effects of cyclosporine on certain endothelial cell functions, namely matrix metalloprotease (MMP)-2 and MMP-9 secretion, proliferation, chemotaxis, and morphogenesis, were investigated in vitro, and its effects on angiogenesis were studied in vivo by using the chick embryo chorioallantoic membrane (CAM) model. In vitro, at low noncytotoxic doses (2, 4, 8, and 16 microg/mL), cyclosporine inhibited all these functions in a dose-dependent manner, although MMP-2 secretion was inhibited only at 16 microg/mL. The absence of cytotoxicity was confirmed morphologically and also because inhibition was rapidly reversed as soon as cyclosporine was removed. In vivo, cyclosporine at 0.012 and 0.024 microg per CAM displayed noncytotoxic, dose-dependent antiangiogenic activity. Biochemically, the drug inhibited the activity of the endothelial cell respiratory chain enzymes succinate oxidase and cytochrome-c oxidase, again in a dose-dependent manner. This finding could explain the effects observed in vitro and in vivo. These antiangiogenic properties of low-dose cyclosporine warrant further investigation in certain autoimmune and neoplastic diseases characterized by enhanced angiogenesis.