Introduction: The purpose of this prospective, randomized, double-blind, placebo-controlled study was to compare the anesthetic efficacy between lidocaine with andwithoutmagnesiumsulfate USP 50%for inferior alveolar nerve (IAN) blocks in patients with symptomatic irreversible pulpitis. Methods: One hundred patients with symptomatic irreversible pulpitis of mandibular posterior teeth were selected for the study. The patients received 1 mL magnesium sulfate USP 50% or distilled water (placebo) 1 hour before administration of conventional IAN block. Endodontic access cavity preparation was initiated 15 minutes after the IAN block injection. Lip numbness was recorded for all the patients. Success of IAN block was defined as no or mild pain on the visual analogue scale during access cavity preparation and initial instrumentation. Results: The success rate for the IAN block was 58% for magnesium sulfate group and 32% for the placebo group, with statistically significant difference between the 2 groups (P = .016). Conclusions: In mandibular posterior teeth diagnosed with symptomatic irreversible pulpitis, preoperative administration of 1 mL magnesium sulfate USP 50% resulted in statistically significant increase in success of IAN block compared with placebo. Copyright © 2015 American Association of Endodontists.