To assess the effect of the biological response to implanted Ag/AgCl reference electrodes on the electrode stability, uncoated and polymer-coated Ag/AgCl electrodes were implanted subcutaneously in rats. After 1 week of implantation, uncoated Ag/AgCl electrode potentials, measured in 0.1 M KCl, shifted by about -180 mV, and both voltammetry and electron microscopy showed that all the AgCl was removed. The electrodes could be significantly protected by coating with polyurethane or a perfluorinated ionomer (Nafion) cured at 120 degrees C for 1 h. Electron micrographs showed the 120 degrees C cured Nafion and polyurethane coatings remained intact over 2 weeks of implantation. Following 2 weeks of implantation the cured, Nafion-coated electrodes' potentials were shifted by -15 +/- 7 mV relative to the initial values. Voltammetry showed that they were still not polarizable. The current densities obtained with the coated reference electrodes are sufficient for their use as counter/pseudoreference electrodes with implantable two-electrode glucose sensor systems. The tissue response to coated electrodes was minimal in comparison to the response to uncoated reference electrodes.