Phenytoin (DPH), a widely used anticonvulsant, has been shown to effect membrane transport in a wide variety of tissues. After injection, DPH is known to accumulate in high concentration in the kidney, however the renal effects of this drug have not been investigated. Therefore, these studies were designed to elucidate the effect of DPH on renal function and renin release. Dogs were anesthetized and had renal venous, aortic, brachial and ureteral catheters placed. During each of three successive experimental clearance periods, either saline, propylene glycol vehicle (V) or V + DPH (0.18 mg/kg/min) was infused via a 23-gauge needle in the left renal artery. In five dogs (Group I), the sequences of infusion was saline, (V) and (V). Five animals (Group II) differed only in that V was infused during all three periods. Seven animals (Group III) underwent sequential infusions of V, V + DPH, and V. Infusion of V alone resulted in a significant increase in systemic blood pressure from 120 to 135 mm Hg (P < .05). Significant increases after V infusion were found in urine volume (0.45 to 0.87 ml/min) (P < .05) and osmolar clearance (1.23 to 1.83 ml/min). Infusion of DPH produced a 22% increase in renal blood flow from 238 to 291 ml/min (P < .05) and a fall in renal vascular resistance from 0.51 to 0.41 mm Hg/ml/min (P < .05). Significant increases were also seen in urine volume from 0.87 to 1.58 ml/min (P < .05), urine sodium excretion (157 to 269 microEq/min) (P < .05) and osmolar clearance (1.54 to 2.62 ml/min) (P < .05). Renal renin secretion rate was unchanged in Group I and II animals but DPH infusion resulted in a 7-fold increase in renin secretion from 21 to 151 ng A-I/hr x min (P < .05). We conclude that intrarenal arterial infusion of DPH results in renal vasodilation, diuresis and natriuresis. Furthermore, this agent also stimulates renin release which may be the result of its effect on membrane transport.