Background: A comparative study is made of the anesthetic efficacy of 4% articaine versus 2% lidocaine, both with epinephrine 1:100,000, in truncal block of the inferior alveolar nerve during the surgical extraction of impacted lower third molars. Study design: A randomized double-blind clinical trial was conducted of 30 patients programmed for the bilateral surgical extraction of symmetrical lower third molars in the context of the Master of Oral Surgery and Implantology (University of Barcelona, Barcelona, Spain). Following the obtainment of informed consent, two operators performed surgery on an extemporaneous basis, using as local anesthetic 4% articaine or 2% lidocaine with the same concentration of vasoconstrictor (epinephrine 1:100,000). The study variables for each anesthetic were: latency (time to action) and duration of anesthetic effect, the amount of anesthetic solution used, and the need of re-anesthetize the surgical zone. A visual analog scale was used to assess pain during surgery, and thus subjectively evaluate the anesthetic efficacy of the two solutions. Results: Statistically significant differences (p = 0.003) were observed in the mean duration of anesthetic effect (220.86 min. for 4% articaine vs. 168.20 min. for 2% lidocaine). Latency, the amount of anesthetic solution and the need to re-anesthetize the surgical field showed clinical differences in favor of articaine, though statistical significance was not reached. The pain scores indicated similar anesthetic efficacy with both solutions. Conclusions: The results obtained suggest that 4% articaine offers better clinical performance than 2% lidocaine, particularly in terms of latency and duration of the anesthetic effect. However, no statistically significant differences in anesthetic efficacy were recorded between the two solutions.