Methods for preventing damage to epithelial tissue during PDT induced using a photosensitizing agent or pre-photosensitizing agent are provided. The methods of the present invention utilize spatial confinement to control photoactivation of the photoactive species to protect the epithelial tissue. In one embodiment, epithelial tissue surrounding a targeted treatment site can be protecting by decreasing the oxygen-content in the tissue, thereby preventing the conversion of the photosensitizer into the phototoxic species in the epithelial tissue.