Vasoactive intestinal peptide (VIP) increased plasma renin activity (PRA) in pentobarbital-anesthetized dogs. A 15-min infusion of VIP directly into the renal artery at a dose of 33 ng . kg-1 min-1 increased renin secretion rate from 1,461 +/- 393 to 5,769 +/- 1,794 ng ANG I . ml-1 . 3 h-1 . min-1, and increased PRA from 19.2 +/- 2.3 to 29.2 +/- 4.7 ng ANG I . ml-1 . 3 h-1. Renal blood flow and creatinine clearance were also increased, whereas plasma potassium concentration and diastolic blood pressure decreased. There was no change in sodium or potassium excretion. When administered intravenously, 33 and 13 ng . kg-1 . min-1 VIP increased PRA. A dose of 3.3 ng . kg-1 . min-1 failed to increased PRA when given intravenously but produced a significant increase in PRA from 22.8 +/- 8.1 to 40.5 +/- 19.4 ng ANG I . ml-1 . 3 h-1 when infused into the renal artery. This increase occurred without any change in plasma potassium concentration or blood pressure. Renin secretion was increased by a two- to threefold increase in plasma VIP; comparable increases in plasma VIP have been reported to be produced by various experimental procedures. The data indicate that VIP increases renin secretion. The peptide appears to act directly on the kidney and may act directly on the juxtaglomerular cells.