We assessed the effect of insulin and atrial natriuretic peptide (ANP) on renal sodium handling in eight patients with sickle cell disease (SCD), who are characterized by loss of vasa recta and long loops of Henle, and matched control subjects. During insulin infusion (50 mU · kg¹ · h¹), fractional sodium excretion decreased by 0.44 ± 0.72% (P = 0.13) in patients with SCD and by 0.57 ± 0.34% (P = 0.002) in control subjects, whereas fractional distal sodium reabsorption increased by 4.1 ± 1.5% (P < 0.001) and 3.0 ± 1.5% (P < 0.001), respectively. Low-dose (0.3 pmol · kg¹ · h¹) ANP infusion did not affect renal sodium handling in patients with SCD but increased fractional sodium excretion by 0.34 ± 0.22% (P = 0.003) in control subjects. High-dose (2 µg/min) ANP increased natriuresis to a similar extent in both groups. Insulin's antinatriuretic effects predominated over the natriuretic effects of low-dose, but not high-dose, ANP. These data suggest that insulin's antinatriuretic effect is localized at a distal tubular site other than the long loops of Henle and that the long loops are involved in the natriuretic effect of low-dose ANP, possibly mediated by changes in medullary blood flow.