Objective: Caveolin-1 (Cav-1) interacts with large conductance Ca2+-activated potassium channels (BKCa) and likely exerts a negative regulatory effect on the channel activity. We investigated the role of Cav-1 in modulating BK(Ca) channel-mediated, endothelium-derived hyperpolarizing factor (EDHF)-dependent arteriolar dilation in normal condition and in experimental model of obesity. Methods and Results: In isolated, pressurized (80 mmHg) gracilis muscle arterioles (~ 100 mm) of Cav-1 knockout mice, ACh-induced, EDHF-mediated dilations were enhanced and were significantly reduced by BK(Ca) channel inhibitor, iberiotoxin (IBTX), while IBTX had no effect on EDHF-mediated dilations in wild type mice. Dilations to selective BK(Ca) channel opener, NS-1619 were augmented in Cav-1 knockout mice. In high fat diet-treated, obese rats ACh-induced coronary arteriolar dilations were preserved, whereas IBTX sensitive, ACh-induced and also NS-1619-evoked vasodilations were augmented, when compared to lean animals. In coronary arterioles of obese rats a reduced protein expression of Cav-1 was detected by Western immunoblotting and immunohistochemistry. Moreover, in coronary arterioles of lean rats, disruption of caveolae with methyl-ß-cyclodextrin augmented IBTX sensitive, ACh-induced, and also NS-1619-evoked dilations. Conclusions: Thus, in normal condition, Cav-1 limits the contribution of BK(Ca) channel to EDHF-mediated arteriolar dilation. In obesity, a reduced expression of Cav-1 leads to greater contribution of BK(Ca) channel to EDHF-mediated response, which seems essential for maintained coronary dilation.