Introduction: The purpose 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 permanent molar with acute irreversible pulpitis, in a randomized, single-blind study. Subjects and Methods: Fifty two patients were included in the study with 26 patients in lidocaine group and 26 patients in articaine group. Patients were given one 600 mg tablet of ibuprofen as a premedication one hour before anesthetic administration. Electric pulp tester reading was recorded before and after anesthesia. Then root canal treatment was done in single visit. Patient rated pain on Visual Analogue Scale (VAS) preoperatively, during access cavity, cleaning and shaping and postoperatively after 6, 12 and 24 hours. Number of analgesic tablets taken was recorded. Chi square test was used to compare between categorical data. Results: There was no statistically significant difference in percent of successful cases between lidocaine (53.8%, 76.9%) and articaine groups (50%, 57.7%) in access and cleaning and shaping, respectively. There was no statistically significant difference in number of patients needed supplemental intrapulpal anesthesia. Most patients reported no or mild pain after 24 hours in both groups and only one tablet was taken when needed. Conclusions: lidocaine inferior alveolar nerve block (IANB) is similar to articaine infiltration in mandibular molars with acute irreversible pulpitis, thus making infiltration with articaine a viable alternative to IANB. Furthermore, supplemental intrapulpal anesthesia proved to be an effective method in controlling pain and finalizing treatment successfully.