The aim of this randomized, double-blinded study was to compare the anesthetic efficacy of 4% articaine with 1:100,000 epinephrine (AE) with 2% lidocaine with 1:100,000 epinephrine (LE) for Gow-Gates blocks and maxillary infiltrations in patients experiencing irreversible pulpitis in mandibular and maxillary posterior teeth. Forty patients diagnosed with irreversible pulpitis of a posterior tooth randomly received either AE or LE by using a Gow-Gates injection or maxillary infiltration. Endodontic access was initiated after no response to Endo-ice 15 minutes after solution deposition. Success was defined as none to mild pain on a visual analogue scale after access. Chi-square and analysis of variance statistical tests were used to analyze the data. Successful endodontic treatment substantially reduced the assessment of pulpitis pain by patients (analysis of variance, P < .0001). Overall anesthetic success in both dental arches was 87.5%. Anesthetic success was not influenced by tooth arch (χ2, P > .7515) or gender (χ2, P > .1115). AE proved to be as effective but not superior to LE (P > .6002). These results demonstrated the similar anesthetic effectiveness of AE and LE when used during the endodontic treatment of teeth diagnosed with irreversible pulpitis.