The administration of 10 mg/kg indomethacin to chronically catheterized near-term sheep resulted in a change in cotyledonary vascular resistance from 0.133 +/- 0.016 to 0.180 +/- 0.022 (mmHg . min)/ml (P less than 0.001). The noncotyledonary uterine vascular resistance increased to 191% of the original value (P less than 0.001) and the renal vascular resistance increased to 147% of the control value (P less than 0.001). The maternal blood pressure increased from 96 +/- 3.4 to 108 +/- 3.4 mmHg (P less than 0.001). Indomethacin (12 mg/kg) was given to nine fetuses, and observations were made in the control condition and at 15, 120, and 240 min. Cotyledonary vascular resistances were 144%, 152%, and 213% of the control values at those times. All changes were significant (P less than 0.03). The umbilical vascular resistance rose slowly throughout the study even though the concentration of indomethacin was falling during that time. These data suggest that this response may be an indirect effect. In the maternal circulation the rapid increase in the cotyledonary vascular resistance seen after indomethacin was probably due to a decreased level of endogenous prostaglandin synthesis.