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Objectives: The aim of this study was to compare the efficacy of apical negative pressure irrigation (ANP) and passive ultrasonic irrigation (PUI) with apical positive pressure irrigation (PP-conventional irrigation) in the periapical repair of dogs' teeth with apical periodontitis. Methods: Forty-nine mesial and distal root canals of premolars of three dogs with experimentally induced periapical lesions were subjected to a single-session root canal treatment. The teeth were randomly assigned to three groups: ANP, PUI, and PP (control). After 180 days, the animals were euthanized, and the anatomic pieces were removed and subjected to histotechnical processing for morphological and morphometric histological analyses of hematoxylin and eosin (HE)-stained sections under conventional and fluorescence microscopy. Periapical lesion size before and 180 days after root canal treatment was measured by periapical radiographic examination. Tartrate-resistant acid phosphatase (TRAP) histoenzymology was performed for osteoclast counting and Brown and Brenn staining to assess bacteria. Data were analyzed statistically by the Kruskal-Wallis test ( α = 5 %). Result: There were no statistically significant differences among the groups regarding periapical lesion size in the radiographic evaluation ( p = 0.91). In the comparison of histopathological parameters, group ANP presented more homogeneous results. There was a statistically significant difference ( p = 0.02) between groups ANP and PP, with better results for group ANP in which milder infiltrate inflammatory was observed. No statistically significant difference ( p > 0.05) was found among the groups with respect to periodontal ligament space, presence of mineralized tissue resorption, size of the periapical lesions, and number of osteoclasts. Conclusion: Although the three irrigation systems elicited similar periapical tissue response with respect to almost all evaluated parameters, ANP presented the mildest inflammatory infiltrate, suggesting an advantage over PP in the indication for clinical use. Clinical relevance: Irrigation of the root canal systems is an extremely important step in root canal treatment. Therefore, it is of relevance to evaluate the efficacy of these systems by in vivo experimental models to provide scientific background for the clinical practice. [ABSTRACT FROM AUTHOR]