Introduction: The objective of this study was to compare the anesthetic efficacy of 2% mepivacaine combined with 100,000 epinephrine with that of 4% articaine combined with 100,000 epinephrine for inferior alveolar nerve blocks during access cavity preparation and root canal instrumentation in patients with symptomatic irreversible pulpitis in mandibular molars, in a randomized clinical trial.Participants and Methods: Sixty-six patients with irreversible pulpitis were admitted to outpatient clinic of Endodontic Department at the Faculty of Oral and Dental Medicine, Cairo University took part in the trial. Patients were randomly allocated to one of two equal groups to receive inferior alveolar nerve block containing 3.6 mL of 2% mepivacaine with 100,000 epinephrine or 3.4 mL of 4% articaine with 100,000 epinephrine. Root canal treatment was started at 15-minutes post injection in presence of profound lip numbness and completed in a single visit. Preoperative pain, pain during access cavity preparation and root canal instrumentation was recorded using a numerical rating scale (NRS).Results: There was no statistically significant difference between anesthetic efficacy of mepivacaine (36.4%) and articaine (46.4%) anesthetic solutions. Regarding the need for supplemental anesthesia, both mepivacaine and articaine anesthetic solutions were similar and (48.4%) of patients in the two groups needed supplemental anesthesia during the treatment.Conclusion: Anesthetic efficacy of 2% mepivacaine was similar to that of 4% articaine (both with 1:100,000 epinephrine) in inferior alveolar nerve blocks. Neither of anesthetic solutions resulted in effective pulpal anesthesia during endodontic treatment of mandibular molars with irreversible pulpitis.