Human erythrocytes possess a proteolytic activity degrading glucagon (and insulin) even at very low concentrations with a high degree of efficiency. The enzyme which likely belongs to the class of insulin-glucagon-proteinases, can be inhibited by chelating agents, such as ethylenediamine tetraacetic acid and o-phenanthroline, thiol blocking reagents, such as p-chloromercuribenzoate and N-ethylmaleimide as well as by proteinase inhibitors directed against serine proteinases, such as Contrykal and Trasylol. No inhibition could be shown by leupeptin. Insulin in an equimolar range is capable of inhibiting glucagon degradation competitively. Dithioerythritol stimulates the degrading activity. Co++, Zn++, Mn++ and Ca++ prevent the o-phenanthroline mediated inhibition of glucagon degrading activity, whereas Mg++, Cu++, Cd++ and Fe+++ have an inhibitory effect. The glucagon degradation exhibits a pH optimum at 7,1 with an apparent Km of 4.4 X 10(-6) mol/l. The insulin-glucagon-proteinase in human erythrocytes is supposed to have a regulatory influence within the carbohydrate pathway.