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INTRODUCTION Obtaining anesthesia of teeth with irreversible pulpitis is one of the most challenging issues in endodontic practice. The aim of this study was to evaluate the effect of anatomical variables on the success rate of anesthesia in maxillary molars with irreversible pulpitis. METHODS Patients who had maxillary molars with irreversible pulpitis and who had already had a cone-beam computed tomographic (CBCT) scan performed were included in this study. After infiltration injection of an anesthetic solution, the success rate of anesthesia was recorded by asking the patients to rate their pain during access cavity preparation and root canal instrumentation as well as their need for a supplementary injection during the treatment. The distance of the palatal root to the buccal cortical plate was calculated by using the Planmeca Romexis Viewer's measuring tools in both the axial and coronal views. Data were analyzed by chi-square and t-tests as well as receiver operating characteristics (ROC) curve analysis. RESULTS Forty-seven maxillary first and second molar teeth were eligible to be included in this study. The overall success rate of anesthesia was 63.80%. The palatal roots that had their apex located more than 12.34 mm from the buccal cortical plate in the axial view and 12.46 mm in the coronal view had a higher chance of anesthesia failure compared to the teeth with smaller distances. The presence of the maxillary sinus between the cortical plate and roots had no significant impact on the efficacy of anesthesia (P>0.05). CONCLUSION The potential of anesthesia failure during treatment of irreversible pulpitis in maxillary molars with a divergent palatal root is significantly higher than in teeth with shorter distances from the palatal root apex to the buccal cortical plate. If a patient has already had a CBCT scan done for other reasons or the CBCT is available in his/her records, a dental practitioner can use it to predict anesthesia success for maxillary molars with irreversible pulpitis.