The self-exchange of chloride isotopes across the human erythrocyte membrane was inhibited by tetracaine, benzocaine, and lidocaine. The inhibition by tetracaine was increased at higher pH values, but was not exclusively due to the uncharged form of tetracaine. The inhibition was effective within 5 seconds, was reversible, was non competitive with chloride ions, and was not reversed by calcium ions. These findings indicate that local anesthetics react with the erythrocyte chloride carrier at a site separate from the chloride site and cause inhibition of anion transport by a specific mechanism not involving changes in the surface charge density on the erythrocyte membrane.