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Profound pulpal anesthesia is difficult to achieve in mandibular molars with irreversible pulpitis (IP). However, there are no published randomized controlled clinical trials comparing the success of supplemental buccal infiltration (BI) in mandibular first versus second molars with IP. The purpose of this prospective, randomized, double-blind study was to compare the efficacy of 4% articaine with 2% lidocaine for supplemental BIs in mandibular first versus second molars with IP after a failed inferior alveolar nerve block (IANB). This study's sample was combined with data from a previous trial.One hundred ninety-nine emergency subjects diagnosed with IP of a mandibular molar were selected and received an IANB with 4% articaine. Subjects who failed to achieve profound pulpal anesthesia, determined by a positive response to cold or pain upon access, randomly received 4% articaine or 2% lidocaine as a supplemental BI. Endodontic access was begun 5 minutes after infiltration. Success was defined as less than mild pain during endodontic access and instrumentation on the Heft-Parker visual analog scale.There was a 25% IANB success rate with 4% articaine. The success rate for articaine supplemental BI in first molars was 61% versus 63% for second molars (P > .05). The success of lidocaine in first molars was 66%, but for second molars it was 32% (P = .004).The success rate for IANB with 4% articaine was 25%. Articaine and lidocaine had similar success rates for supplemental infiltration in first molars, whereas articaine was significantly more successful for second molars. However, because BI often did not provide profound pulpal anesthesia, additional techniques including intraosseous anesthesia may still be required.