Somatostatin (SRIH) receptors were identified in human kidneys by in vitro receptor autoradiography using 125I-[Tyr3]octreotide and 125I-[Leu8,D-Trp22,Tyr25]SRIH-28 as radioligands. Characterization of the binding demonstrated a single class of high affinity binding sites with a dissociation constant (Kd) of 0.5 nmol/L. Binding depended on GTP and magnesium and sodium concentrations. SRIH-14, SRIH-28, and octreotide were able to displace the radioligand in the high affinity range, whereas biologically inactive SRIH analogs or unrelated peptides were not. Microscopic localization of these receptors revealed binding over cortical and medullary areas. In the cortex, the receptors were located in the proximal tubules. No SRIH receptors were found in the glomeruli. In the medulla, the receptors were identified in high density in medullary vasa recta. A diffuse labeling of lesser density observed in the remaining medulla corresponded to collecting tubules. The receptor concentration was 32 fmol/mg protein in the renal cortex and 304 fmol/mg protein in the vasa recta. The receptors were undetectable in the rat kidney and are, thus, species dependent. SRIH receptors in the human kidney may be the molecular basis for the actions of SRIH on renal functions and may indicate a therapeutic potential for SRIH analogs in this tissue.