Endothelial dysfunction is proposed to be involved in the development of cardiovascular diseases (CVDs) but marked relaxing responses to shear stress can be observed in coronary resistance arteries (rAs) of CVD patients. We tested whether responses to endothelium-dependent agonists are also maintained in more peripheral rA of CVD patients. A biopsy of the parietal pericardium was obtained during coronary artery bypass and/or cardiac valve related surgery. From this tissue, we isolated rA segments (Ø at 100 mmHg: 198 ± 8 μm; n = 134, N = 37) that were investigated in wire myographs. During contraction induced by an EC50 concentration (2 nM) of endothelin-1 (ET-1, Emax: 1.5 ± 0.1 N/m), acetylcholine (EC50 and Emax: 148 ± 28 nM and 70 ± 3 %), bradykinin (EC50 and Emax: 1.8 ± 0.1 nM and 110 ± 1 %) and insulin (EC50 and Emax: 10 pM and 105 ± 13 %) induced potent and marked relaxing responses, in spite of the CVD profile of the patients. The relaxing responses to the endothelium-dependent agonists were not significantly reduced by the combined presence of 100 μM L-NAME (NOS-inhibitor), 10 μM indomethacin (COX-inhibitor), 1 μM UCL 1684 and 1 μM TRAM-34 (inhibitors of small- and intermediate conductance calcium-activated potassium channels) plus 10 μM ODQ (inhibitor of soluble guanylate cyclase). Our observations suggest compensatory upregulation of alternative vasodilator pathways in peripheral resistance arteries of CVD patients. The mechanisms of these pathways remain to be established.