Intrarenal artery infusions of low-dose human, but not mouse, leptin cause diuresis/natriuresis in rats [E. K. Jackson and P. Li. Am. J. Physiol. 272 (Renal Physiol. 41): F333-F338, 1997]. The lack of effect of mouse leptin in the rat could be due to slight differences in the primary structure of mouse vs. rat leptin. To test this hypothesis, we infused single doses of rat (0.1, 0.3, 1, or 3 µg/min) or human (3 µg/min) leptin into the renal artery of rats for 140 min while continuously measuring blood pressure and the renal excretion rate of urine and electrolytes. Intrarenal infusions of rat leptin did not alter any measured parameter. Human leptin caused a delayed diuresis/natriuresis (P < 0.0006 and P < 0.0049, respectively) that required ~2 h to achieve a maximum effect and that was not accompanied by changes in blood pressure or potassium excretion. We conclude that low-dose human, but not low-dose rodent, leptin has direct diuretic/natriuretic activity. Our results can be explained from an evolutionary perspective, since obesity-induced hypertension would be a much greater selective force in hominids compared with rodents.