The fate of plasma glucagon has been analyzed in detail by Desbuquois and Postel-Vinay. The present work was carried out to clarify the relationships between plasma glucagon disappearance and its tissue uptake. For the purpose, we injected rats intravenously with 125I-glucagon alone or with concomitant or sequential injections of native glucagon. Plasma 125I-glucagon was analyzed by Biogel P10 chromatography. Liver and kidney glucagon kinetics were studied from the point of view of the evolution of the total radioactivity present in each tissue a few minutes after glucagon injection. 125I-glucagon was rapidly cleared from the plasma (half-life within 2 min); it was intensively associated with liver and kidneys. Liver radioactivity rapidly declined within the first 5 min after injection, whereas kidney radioactivity increased. The concomitant injection of increasing amounts of native glucagon with 125I-glucagon progressively reduced the liver radioactivity, indicating that glucagon was trapped in a saturable compartment. In contrast, kidney radioactivity remained unchanged. The sequential injection of 125I-glucagon and excess native glucagon resulted in a shift to the right in the plasma 125I-glucagon decay curve which suggests that the glucagon excess displaced 125I-glucagon from its distribution compartment back into the plasma. The compartment where glucagon uptake occurred a few minutes after 125I-glucagon injection displayed some of the fundamental properties of glucagon receptors, i.e. saturatibility and reversibility.