The effectiveness of Passive Ultrasonic Irrigation(PUI) and Sonically Activated Irrigation(SAI) techniques was investigated in apical periodontitis(AP) patients based on changes in prostaglandin E2(PGE2), nitric oxide(NO), and interleukin-6(IL-6) levels. Sixty-six AP patients and thirty healthy controls were enrolled. Preoperative gingival crevicular fluid(preGCF) PGE2, NO and IL-6 levels were measured before treatment. After chemo-mechanical preparation, teeth were assigned into two groups according to final irrigation protocol[PUI(n:33) and SAI(n:33)]. The same markers were again measured 1 week after treatment(postGCF) and also 1st order most commonly seen bacteria(FMCB) typing was performed on microbial samples of the patients. PostGCF-PGE2 levels of the PUI group were lower than postGCF-PGE2 levels of the SAI group(p = 0.0335). Both postGCF-PE2 and IL-6 levels of the PUI group were significantly decreased after treatment(p < 0.0001), while only postGCF-PE2 levels decreased in the SAI group(p = 0.0316). The PUI system significantly reduced PGE2 and IL-6 levels by better controlling inflammation in the treatment of AP.