The direct response of AgzS crystal membrane electrodes to sulfur-containing proteins has been investigated using model compounds of varying disulfide and sulfhydryl content. Potentiometric measurements on solutions of the proteins lysozyme, ovalbumin, human serum albumin, and ribonuclease A show clear relationships between electrode response and protein conformation. Studies involving denaturation and refolding of model proteins demonstrate that electrode response is a function of the free sulfhydryl content of proteins and not of disulfide linkages. The mechanistic information obtained lays the groundwork for the analytical use of AgzS electrodes for the direct measurement of proteins in solution.Recently, ion selective electrodes have found increasing use