Urocortin 2 (Ucn2) - corticotropin-releasing hormone receptor 2 signalling has favourable effects in the cardiovascular system, including vasodilation, lowering of blood pressure and systemic peripheral resistance, increase in cardiac output and cardiac contractility, as well as cardioprotection against ischemia-reperfusion injury. Vasodilation and lowering of blood pressure seem to be very interesting and important effects, but their mechanism and interaction with the antihypertensive drugs have not been evaluated. The aim of the present study was to assess the relationship between Ucn2 concentration and antihypertensive therapy in patients with primary hypertension. We examined a group of 65 patients with primary hypertension receiving at least 3 antihypertensive drugs. In all of them plasma level of Ucn2, anthropometric measurements, biochemical tests, ambulatory blood pressure monitoring (ABPM), and echocardiography were performed. There were no differences in Ucn2 level related to beta-blockers, calcium channel blockers or diuretics, but we observed that in patients treated with angiotensin converting enzyme inhibitors (ACEI) (n = 52) serum Ucn2 levels were significantly higher than in patients treated with angiotensin-receptor blockers (ARBs) (n = 13) (10.93 versus 5.56 ng/mL; P < 0.05). Moreover, we did not observe any differences in terms of blood pressure on ABPM, biochemical measurements, left ventricular mass index, or presence of diabetes. In addition, in a small subgroup receiving alpha-blockers we also found a lower level of Ucn2, with coexisting higher systolic blood pressure at night, higher left ventricle mass index (LVMI) and more frequent occurrences of diabetes compared to non-alpha-blockers. Our findings suggest that the hypotensive action of renin-angiotensin-aldosterone system blockade may be related to the urocortin system. Ucn2 may be an important element in the mosaic of blood pressure-lowering factors in patients treated for essential hypertension.