Abstract : Microorganisms are capable initiators of the host immune responses in periapical tissues via root canal systems. Therefore, the pathogenic process is related to the virulence of bacteria and to the host's resistance. Microbiological investigations revealed the micro biota of human infected root canals as being polymicrobial and anaerobic. Periapical exudates via root canals were found to contain inflammatory mediators produced in the periapical lesions to reflect the immune responses occurring. The temporal context of lesion activity was associated with quantitative differences in inflammatory mediators. The association of immunological changes in periapical lesions and the presence of clinical symptoms of the involved teeth was also suggested. A retrospective study was carried out to evaluate the potential of clinical risk factors as being markers of recurrent periapical lesions. Intracanal findings which can reflect the qualitative and quantitative differences of root canal infections may serve as clinical risk factors of recurrent periapical periodontitis. Further studies are required to reveal the regulatory mechanisms which control the disease activity of periapical lesions. However, microbiological and immunological investigations may provide a new conceptual diagnosis of periapical periodontitis.