Objective: The aim of the present study was to assess effect of 4% articaine infiltration versus 2% lidocaine nerve block after premedication by ibuprofen on anesthetic efficacy in endodontic treatment of first mandibular permanent molar with acute irreversible pulpitis in a randomized clinical trial. Subjects and Methods: Fifty-two patients actively experienced pain diagnosed to be irreversible pulpitis of a mandibular molar tooth accepted to participate in this single-blinded study and underwent single visit endodontic treatment. All patients were equally distributed in control and experimental group. Every patient received 4% artiacine as buccal infiltration or 2% lidocaine as inferior alveolar nerve block (IANB) after one hour from receiving ibuprofen 600mg as premedication. Endodontic access was initiated after 10 minutes of anesthesia, lip numbness and electric pulp tester (EPT) reading. Pain during endodontic access cavity preparation and cleaning and shaping was recorded by visual analogue scale (VAS). When patients needed, they received intra-pulpal anesthesia of the same anesthetic solution as supplemental. All the data were collected and tabulated. Statistical analysis was performed by Microsoft Office 2013 (Excel), the significant level was set at P ≤ 0.05. Statistical analysis was done by Chi square test for categorical data. Results: There was no statistically significant difference between lidocaine group (42.3%, 76.9%) and articaine group (53.8%, 69.2%), in success of pain control during access cavity preparation and cleaning and shaping, respectively. Conclusions: On the basis of the results of this study, it can be concluded that: The 4% articaine buccal infiltration and 2% lidocaine inferior alveolar nerve block have the same anesthetic efficacy in mandibular first molar with irreversible pulpitis after premedication with ibuprofen.