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This randomized crossover double-blind trial compared the efficacy of buccal infiltration with 4% articaine and 2% lidocaine (both with 1:100,000 epinephrine) in securing mandibular first molar pulp anesthesia. Injections were given at least 1 week apart in 31 healthy adult volunteers. Electronic pulp testing was undertaken at baseline and at 2 minute intervals until 30 minutes postinjection. A successful outcome was recorded in the absence of pulp sensation on two consecutive maximal pulp tester stimulations (80 μA). 64.5% of articaine and 38.7% of lidocaine infiltrations were successful (p = 0.008). Articaine infiltration produced significantly more episodes of no response to maximum stimulation in first molars than lidocaine (236 and 129, respectively, p < 0.001). Mandibular buccal infiltration is more effective with 4% articaine with epinephrine compared to 2% lidocaine with epinephrine. Both injections were associated with mild discomfort.