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This study sought to determine the anesthetic efficacy of 4% articaine with 1:100,000 epinephrine in patients with symptomatic and asymptomatic irreversible pulpitis in mandibular posterior teeth and if individual patient factors, pulpal disease characteristics, and previous medication are correlated to local anesthetic success. A second objective was to determine the specificity and sensibility of a cold test for prediction of anesthetic success prior to endodontic treatment. Seventy patients diagnosed with irreversible pulpitis in mandibular posterior teeth received 1.6 mL of 4% articaine with 1:100,000 epinephrine for an inferior alveolar nerve block (IANB) using a metal guide. The anesthetic solution was injected with a computer-preprogrammed delivery system for local anesthesia. Endodontic access was begun 15 minutes after solution deposition; later, patients rated their discomfort using the visual analog scale (VAS). The success rate for the IA NB using articaine was 64.2% in patients with symptomatic irreversible pulpitis and 86.9% in patients with asymptomatic irreversible pulpitis. Cold test prior to root canal treatment had a specificity and sensibility of 12.5% and 87.1%, respectively. The anesthetic efficacy of articaine in irreversible pulpitis is moderately acceptable, and anesthetic success increases when the patient has been premedicated with NSAIDs. The cold test appears to be a favorable indicator for predicting anesthetic success.