The effect of propranolol on normal human red cells was studied in order to evaluate propranolol''s effect on pathological cells. Normal human erythrocytes lost 40 meq of K, decreased the intracellular pH by 0.06 units, and shifted the oxyhemoglobin dissociation curve 6.0 mm Hg to the right in the presence of propranolol. The series of events and magnitude of the response induced by propranolol was time dependent and sensitive to temperature, pH, drug concentration and erythrocyte concentration. Ca was an absolute requirement for maximal propranolol action with simultaneous incorporation of trace amounts of radioactive Ca into the cell. Chelation of Ca with EDTA or EGTA [ethylene-bis-(oxyethylenenitrilo)-tetra-acetic acid] inhibited the response to propranolol.