In 14 patients with Parkinson's disease on long-term therapy the erythrocyte catechol-O-methyltransferase activity was found to correlate with the average plasma concentration ratio of 3-O-methyldopa to levodopa and with the fasting plasma concentration ratio of 3-O methyldopa to levodopa. Patients with the higher erythrocyte catechol-O-methyltransferase activities were those with less favorable clinical responses to levodopa. Since erythrocyte catechol-O-methyltransferase activity may reflect the activity of that enzyme in the major metabolizing tissues, catechol-O-methyltransferase activity would seem to be a significant determinant of response to levodopa.