We investigated the effects of clinically comparable doses of ibuprofen and indomethacin on renal, gastrointestinal and cerebral perfusion in newborn piglets, and hypothesized that ibuprofen would have less effect on regional circulation. Animals were randomly assigned to receive ibuprofen (20 mg/kg, n = 8), indomethacin (0.3 mg/kg, n = 7) or vehicle (n = 6). Fluorescent microspheres were injected prior to and at 20, 40, 60, 90 and 120 min after drug administration. Regional blood flow was measured and vascular resistances were calculated. Cardiovascular and respiratory variables were not significantly affected by either study drug or vehicle. Ibuprofen increased renal cortical and medullary resistance by 44 and 52% (p < 0.05). However, ibuprofen had no significant effects on gastrointestinal or cerebral resistance. Indomethacin raised renal cortical and medullary resistance by 66 and 71% at 60 min postinjection, respectively (p < 0.05). Indomethacin increased duodenojejunal, ileal and colon resistance by 97, 102 and 75% at 60 min, respectively (p < 0.05). Indomethacin increased cerebral cortical and cerebellar resistance by 92 and 86% at 90 min (p < 0.05). While indomethacin and, to a lesser extent, ibuprofen both increase renal vascular resistance, indomethacin vasoconstricts the gastrointestinal and cerebral circulations which are unaffected by ibuprofen.