The effects of indomethacin and ibuprofen on aortic blood pressure and regional vascular resistances were studied in pentobarbital-anesthetized dogs. In the mesenteric vascular bed, indomethacin produced severe, acute vasoconstriction when administered by i.v. infusion as well as by i.a. injections. Tachyphylaxis developed rapidly to this response. In contrast. ibuprofen did not alter mesenteric blood flow even when a large (50 mg) i.v. bolus was rapidly injected. The mesenteric vasoconstrictor response to indomethacin was not modified when prostaglandin synthesis was inhibited or in the presence of cyproheptadine. Phentolamine exerted only a minor influence on the mesenteric vascular effect of indomethacin. The effects of indomethacin and ibuprofen on aortic blood pressure and renal blood flow were similar. Both agents increased aortic pressure and decreased renal blood flow a small but significant amount, but these responses occurred slowly and were probably not related to the acute mesenteric vasoconstricting effect or indomethacin. The present study demonstrates that these nonsteroidal anti-inflammatory agents have different effects on the mesenteric vascular bed and the data suggest that the vasoconstricting effects of indomethacin are not related to the inhibition of prostaglandin synthesis in the intestine. The data also suggest that the acute vasoconstriction in the mesenteric circulation produced by indomethacin is not mediated to a significant degree by local release of alpha adrenergic agents or serotonin.