In the final trimester of both human and rabbit pregnancy, circulating PGE2 and PRA are increases. The sequence of the increase in PGE2 and its relationship with the rise in PRA have not been studied. In this study we measured serum and urinary PGE2 as well as PRA and creatinine clearance during five 6-day periods throughout rabbit pregnancy. Serum PGE 2 was increased by days 13 through 18 of the 30-day pregnancy. The increase in PRA lagged behind, not occurring until days 19 through 24. Serum PGE2 and PRA seemed to rise further as pregnancy progressed. Urinary PGE2 also rose during pregnancy and paralleled an increase in creatinine clearance. These changes were noted by days 19 through 24, but no further increments were apparent. Administration of indomethacin to a separate group of rabbits between days 21 through 24 of pregnancy decreased urinary PGE2 and PRA but did not reduce either serum PGE2 or creatinine clearance. The time course of the rise in serum PGE2 defined by these studies is consistent with this compound having a possible role in mediating the altered renal hemodynamics of pregnancy. The increase in PRA followed in time the rise in circulating PGE2, suggesting it might be a consequence of enhanced PGE2 synthesis. Renal PGE2 production is also increased during rabbit pregnancy, but the study with indomethacin appears to exclude a primary role for renal PGE2 in the supranormal kidney function of pregnancy.