Washed human red cells, suspended in an isotonic electrolyte solution, were incubated with radioactive catecholamines (epinephrine, norepinephrine, dopamine and isoproterenol). Their conversion to 3-O-methyl derivatives was demonstrated by ion exchange chromatography for each substrate. There was no O-methylation if the erythrocytes were boiled or hemolyzed prior to incubation or if the catechol-O-methyl transferase (COMT) inhibitor pyrogallol was added to the incubation medium. Only catecholamines were methylated by this system, as could be demonstrated by using the non-catecholamine orciprenaline as substrate. Experiments with l-methionine-(methyl-14C) showed that the methylation was brought about by the transfer of a methyl group from l-methionine to the 3-hydroxy group of epinephrine. Thus, this enzymatic system had the properties of COMT. Our experiments therefore suggest that COMT is present in human erythrocytes.