We report on a hybrid photoanode for water oxidation consisting of a cyanobacterial photosystem II (PSII) from Thermosynechococcus elongatus on a mesoporous indium-tin oxide (mesoITO) electrode. The three-dimensional metal oxide environment allows for high protein coverage (26 times an ideal monolayer coverage) and direct (mediator-free) electron transfer from PSII to mesoITO. The oxidation of water occurs with 1.6 +/- 0.3 mu A cm(-2) and a corresponding turnover frequency of approximately 0.18 +/- 0.04 (mol O-2) (mol PSII)(-1) s(-1) during red light irradiation. Mechanistic studies are consistent with interfacial electron transfer occurring not only from the terminal quinone Q(B), but also from the quinone Q(A) through an unnatural electron transfer pathway to the ITO surface.