We examined the presence of the receptor for advanced glycation end products (RAGE) in periapical granulomas and analyzed the interaction between RAGE and inducible nitric oxide synthase (iNOS) to elucidate inflammatory reaction mechanisms. Periapical lesions were surgically removed from 37 patients with chronic periapical periodontitis and halved. Paraffin sections were prepared from half of each lesion and stained with hematoxylin and eosin, whereas cryostat sections were prepared from the other half. Based on the histological evaluation, 33 of the lesions were diagnosed as periapical granulomas. These were examined by immunohistochemistry using serial cryostat sections probed with anti-human iNOS or RAGE antibodies. Macrophages, lymphocytes, and endothelial cells expressed RAGE and these cell types, in addition to plasma cells, exhibited anti-iNOS immunoreactivity. Serial cryostat sections demonstrated the infiltration of RAGE-expressing cells around iNOS-producing cells, suggesting that these molecules may be important in the tissue injury associated with periapical periodontitis.