Human red blood cells (RBC) contain a monoester lipase (MEL) activity which is tightly associated with the cell membrane and has its active site externally oriented, as inferred from the ability of the intact cell to hydrolyse an exogenously added lipid substrate. Membrane-bound MEL activity was measured by a radiochemical assay in intact RBC from 29 untreated hyperthyroid patients. The mean (+/- S.D.) MEL level was higher (P less than 0.01) in these patients (1220 +/- 212 mu./10(12) RBC) than in the control group (1010 +/- 120 mu./10(12) RBC). There was no difference between men and women. The increase in MEL values was associated with significantly (P less than 0.001) decreased values of mean cellular volume and mean cellular haemoglobin content. A continued study of 13 patients, who became euthyroid with treatment, showed a normalization of the MEL values in RBC. The increased lipolytic potency of RBC represents a new characteristic of hyperthyroid patients. Further exploration of the possible diagnostic or prognostic implications of this enzymatic change seems warranted.