The binding of human calcitonin (CT) was investigated in the plasma membrane fraction obtained from normal rat liver. The liver plasma membrane bound 125I-labeled [( 125I]) human CT, with increasing concentrations of the plasma membrane protein from 4.6-80 micrograms/ml, in a both time and temperature dependent manner. Specific binding of [125I] human CT was competitively inhibited by concentrations of unlabeled homologous hormone more than 0.05 nM. Half-maximal inhibition of specific binding was observed with 0.5 nM human CT. Scatchard analysis of the data suggested the presence of one class of binding site with an apparent affinity constant of 4.08 X 10(9)M-1. The binding of human CT was highly specific; half-maximal inhibition of binding was observed with 100 nM synthetic [Asu1,7] eel CT, ACTH having no effect in this system. These results demonstrate that specific binding receptor sites for CT are present in the plasma membrane of rat liver, compatible with the CT function in these cells.