Background <p>This retrospective cohort study aimed to assess clinical outcomes and identify prognostic factors of endodontic microsurgery through cone-beam computed tomography (CBCT) analysis.</p> Methods <p>Seventy-one teeth diagnosed with apical periodontitis and indicated for endodontic microsurgery were included. Two endodontic specialists performed the surgery following a standardized protocol. Clinical and radiographical reevaluations were conducted at least one year postoperatively. Two examiners independently measured the periapical radiolucency volumes before and after surgery from CBCT scans. Radiographic healing was classified as complete, limited, uncertain, or unsatisfactory. Multivariate logistic regression was used for prognostic analysis.</p> Results <p>Sixty-three teeth (88.7%) were available for follow-up; Sixty-two teeth (Sixty-one asymptomatic) were included in the final prognostic analysis. One tooth was excluded because it was extracted after the metal post-and-core fell off. The volume of periapical radiolucency measured at the final follow-up (≥ 1 year) showed a mean reduction of 89.4% compared to preoperative volumes (95% CI: 78.9% to 99.99%; <i>P</i> &lt; .001). Complete or limited healing was observed in 53 teeth (85.5%), while 9 teeth (14.5%) showed uncertain or unsatisfactory healing. The angle of root resection was identified as a significant prognostic factor (<i>P</i> &lt; .05).</p> Conclusion <p>This retrospective study provided information about the outcomes and prognostic factors of endodontic microsurgery, so as to detect the disease prognosis trend as early as possible, pre-plan the next treatment strategy, and effectively avoid prognostic factors that affect clinical outcomes.</p>