Nonsteroidal anti-inflammatory drugs (NSAIDs) can induce an increase in blood pressure (BP) and may potentially reduce the efficacy of several antihypertensive drugs. Probably the main mechanism of action is inhibition of prostaglandin (PG) synthesis since NSAIDs have higher propensity to increase BP as the regulation of BP (and renal function) is more PG-dependent and to interact with drugs (diuretics, beta-blockers and ACE inhibitors) that may act through the increase of PG formation. In contrast, NSAIDs do not interact with calcium antagonists and central acting drugs which actions are apparently unrelated with renal/extrarenal production of PG. It has been claimed that inhibition of natriuretic PGs could explain the pressure effects of NSAIDs in treated hypertensive patients, but sodium retention may be not the single explanation for such an interaction. We found that despite indomethacin produced sodium retention after being added either to enalapril or nifedipine-GITS, it only attenuated (by 45%) the antihypertensive effects of enalapril. In alternative, since PG enhances vasodilatation and attenuates vasoconstrictor influences, some NSAIDs may counteract the PG-dependent vasodilatory tone in renal and extrarenal vascular beds that mediate the antihypertensive action of some drugs. Thus, since calcium antagonists are probably not affected by NSAIDs, they may be preferable to drugs like diuretics, beta-blockers and ACE inhibitors for the treatment of high blood pressure control in hypertensive patients who are clinically suitable for NSAIDs therapy.