BACKGROUND No study has compared lidocaine with articaine, each at a concentration of 4% and combined with epinephrine. The purpose of this study was to compare the effectiveness of 4% lidocaine with that of 4% articaine, with a concentration of 1:100,000 epinephrine added to each, in an inferior alveolar nerve block for surgery on impacted lower third molars. METHODS This study was conducted at the Faculty of Dentistry, Mahidol University in Bangkok, Thailand. The randomized, single-blind, comparative split-mouth study was carried out in patients with symmetrically impacted lower third molars, as identified on panoramic radiographs. Each patient underwent surgery for the removal of the lower third molars by the same surgeon under local anesthesia at two separate visits, 3 weeks apart. The onset and duration of local anesthesia, intra-operative pain, surgical duration, and number of additional anesthetics administered were recorded. RESULTS The subjective and objective onset of action for the local anesthetics showed statistically significant differences (P < 0.05). However, the intra-operative pain, surgical duration, duration of local anesthesia, and number of additional anesthetics administered did not show statistically significant differences. CONCLUSIONS The use of 4% articaine for the inferior alveolar nerve block was clinically more effective in the onset of subjective and objective anesthesia as compared with the use of 4% lidocaine. Based on the pain scores from the visual analogue scale, 4% lidocaine provided more analgesia during the procedure, and patients noted less intra-operative pain than with 4% articaine; however, the difference was not clinically significant.