OBJECTIVES: The purpose of this systematic review was to appraise the existing literature on the effect of hard tissue defects on the clinical outcome of endodontic microsurgery (EMS). METHODS: MEDLINE (PubMed), Embase, Web of Science, Cochrane Library and grey literature were searched from January 2000 to May 2023. Study selection and data extraction were performed in duplicate. Eligible studies were critically appraised for the risk of bias using the Cochrane Risk of bias tool. The quality of evidence was assessed using GRADE. Review Manager (RevMan Computer program Version 5.4, The Cochrane Collaboration, 2020) was utilized and the Mantel Haenszel fixed or random effects model was applied, depending on the heterogeneity of the studies. Meta-analysis was performed to estimate the Risk ratio (RR) and 95% Confidence Interval (CIs) to correlate the effects of these factors on treatment outcomes. RESULTS: Nineteen studies were included. The EMS overall pooled success rate was 84.5%. Five characteristics of hard tissue were identified. The size of the lesion (Small ≤ 5 mm: 78.4% vs. Large > 5 mm: 63.3%, RR = 1.12, 95% CI 1.00-1.26, P ≤ .05), significantly affected the outcomes of EMS. Endodontic lesions exhibited slightly better outcomes than endodontic-periodontal lesions (81.4% vs. 68.2%, RR = 1.14 95% CI 0.98-1.33, P > .05). Cases with the height of the buccal bone > 3 mm also exhibited slightly better outcomes (91.5% vs. 71.4%, RR = 1.20, 95% CI 0.88-1.62, P > .05). Additionally, through and through lesions exhibited better outcomes when grafting was completed during the EMS procedure both in 2D (RR = 1.12 95% CI 0.97-1.29, P > .05) and 3D evaluation ((RR = 1.28 95% CI 0.69-2.37 P > .05). The overall quality of evidence was graded as low to high. CONCLUSION: With a low to high quality of evidence, the size of the lesion is a key prognostic variable that significantly affects the outcome of EMS, as lesions ≤ 5 mm exhibit better outcomes as compared to larger lesions. CLINICAL SIGNIFICANCE: The presence of hard tissue defects can affect the outcome of endodontic microsurgery (EMS). The presented data can aid the clinicians decision-making process by examining certain pre-operative prognostic variables, when considering EMS as a treatment option. Clinical cases with more favorable hard tissue characteristics lead to a better prognosis in EMS.