Objectives: The aim of this prospective randomized clinical trial was compare between 2% Mepivacaine and 4% Articaine for inferior alveolar nerve blocks in patients with symptomatic irreversible pulpitis in mandibular molars as regards to their anesthetic efficiency; during access cavity preparation and instrumentation.Subjects and Methods: Sixty-six patients diagnosed clinically and radiographically with symptomatic irreversible pulpitis in mandibular posterior teeth received single-visit root canal treatment using ProTaper Universal rotary system for canal preparation, they were randomly divided into two groups (n=33) according to the anesthetic solution used, either Group M (3.6 ml Mepivacaine hydrochloride 2% with 1:100000 epinephrine) or Group A (3.4 ml Articaine hydrochloride 4% with 1:100000 epinephrine). The pain was assessed using numerical rating scale (NRS) during access cavity preparation and instrumentation, then the need for supplemental anesthesia was also recorded. Results: There was no statistically significant difference in pain level between both groups at the different observation times. The success rates were similar in both groups (39.4% and 45.5% in Mepivacaine and Articaine groups respectively) with no difference in the need for supplemental anesthesia in both groups.Conclusion: The anesthetic efficacy of Mepivacaine and Articaine seemed to be similar, although both did not provide acceptable rate of anesthetic success.