The electrochemical response of activated iridium oxide (AIROF) electrodes implanted acutely in the subretinal space of the rabbit is compared with in vitro measurements in model electrolytes. Voltage transients during current pulsing, cyclic voltammetry, impedance spectroscopy and open-circuit potential measurements were compared. Subretinal charge injection by constant current pulsing required significantly greater driving voltages due to both higher access resistances (iR) and large electrochemical polarization across the electrode-tissue interface. Differences in the in vivo and in vitro open-circuit potentials were also noted. The data suggest that the buffering capacity in the subretinal space, at least in the acute study, is higher than that in inorganic models of interstitial fluid. Possible origins of these differences in terms of electrode-tissue interactions are discussed.