Multiple cancers frequently occur in the upper digestive tract. One possible explanation is that specific bacterial infection stimulates the normal epithelium to initiate inflammation and/or promotes carcinogenesis. This study was undertaken to determine which bacterial species is predominantly associated with esophageal cancer. We examined the bacterial diversity in this type of cancer and in the saliva from healthy people by using a cultureindependent molecular method. Here we report the preferential and frequent infection of the oral periodontopathic spirochete Treponema denticola (T. denticola), Streptococcus mitis (S. mitis), and Streptococus anginosus (S. anginosus) in esophageal cancer from different regions of the world, and we also describe the induction of inflammatory cytokines by infection of S. anginosus and S. mitis. Our present data suggest that these three bacteria could have significant roles in the carcinogenic process of many cases of esophageal cancer by causing inflammation and by promoting the carcinogenic process, and that eradication of these three bacteria may decrease the risk of recurrence. acterial and viral infections are important factors in cancer development. Helicobacter pylori (H. pylori) is reportedly associated with gastritis, gastric atrophy, and gastric cancer, [1][2][3] and the presence of microorganisms has recently been investigated in several kinds of human cancers, while Streptococcus anginosus (S. anginosus) DNA fragments were frequently found in DNA samples from esophageal cancer tissues, gastric cancer tissues, and dysplasia of the esophagus, 4,5) suggesting that S. anginosus infection occurs at an early stage of esophageal cancer and is related to esophageal and gastric carcinogenesis. S. anginosus is classified as an oral bacterium and can be isolated from several parts of the body, such as the oral cavity, gastrointestinal tract, and genitourinary tract. It is often associated with pyogenic infections, including endocarditis.6-8) S. anginosus DNA has also been found in head and neck squamous cell carcinomas, 9) but much less frequently in non-cancerous tissues of the esophagus, and is not present in colon, lung, bladder, renal, and cervical cancer tissues.5) This suggests that S. anginosus DNA is associated with cancers in the upper digestive tract, although the involvement of S. anginosus infection in the carcinogenic process has not been clarified.It is generally accepted that the upper digestive tract is a region in which multiple primary cancers occur at a high rate. Squamous cell carcinoma of the oral cavity is often accompanied with other squamous cell carcinomas of the digestive tract, such as oropharyngeal cancers or esophageal cancers.10, 11) The high incidence of multiple carcinomas in this region is often explained by the concept of field cancerization, which is based on the hypothesis that exposure to carcinogenic agents leads to independent carcinogenesis in epithelial cells at different sites in this region. Although little is known about this hypoth...