Aging is associated with reduced endothelial function. There is indirect evidence for reduced prostacyclin (PGI2)-mediated vasodilation with aging, but it is unknown whether this is because of reduced dilation to PGI2 or altered production. In addition, the contribution of endothelial NO to PGI2-mediated dilation is unknown. Using plethysmography to determine forearm blood flow, we studied the effect of PGI2 in 10 older (61 to 73 years) and 10 younger (19 to 45 years) subjects using 3 escalating intra-arterial doses of PGI2 (epoprostenol). PGI2 was also administered after NO synthase inhibition with NG-monomethyl-l-arginine acetate. The percent of change in forearm vascular conductance (mean±SEM) from baseline after PGI2 was significantly lower (P=0.002) in the aging individuals (52±11%, 164±23%, and 221±27% versus 115±20%, 249±19%, and 370±35%). In addition, the group-by-dose interaction was also significant (P=0.018). After NO synthase inhibition, the dose-response curve to PGI2 was blunted in the young subjects but unchanged in the older subjects; the difference between the groups was no longer significant. Our data suggest that the reduced dilator effects of PGI2 in older individuals are attributable to a reduction in the contribution of endothelial-derived NO versus alterations in the direct effects of PGI2 on vascular smooth muscle.