Recently, it has been demonstrated that leptin, the product of the ob gene, playing a key role in the regulation of body weight, is angiogenic in vitro and in vivo. In this study we investigated the angiogenic potential of human leptin in vivo by using the chick embryo chorioallantoic membrane (CAM) assay, with the aim to establish whether this angiogenic activity is partly dependent on endogenous fibroblast growth factor-2 (FGF-2), which is normally expressed during CAM development. Results showed that leptin is able to stimulate angiogenesis and that the angiogenic response is similar to that obtained with FGF-2. The stimulating property of leptin is specific, as the application of anti-leptin antibodies onto the CAM significantly inhibits the angiogenic response. Moreover, this angiogenic activity is in part due to the activation of endogenous FGF-2. The application of anti-FGF-2 antibodies reduces the angiogenic response to leptin by 40%. Our study confirms that leptin is angiogenic in vivo and suggests that, at least in the chick CAM, its activity is in part mediated by the activation of endogenous FGF-2.