Additional studies are needed to evaluate intraseptal anesthesia in the mandibular first molar. The purpose of this study was to compare the anesthetic efficacy of a primary intraseptal injection of articaine and lidocaine, administered with a computer-controlled local anesthetic delivery (CCLAD) system, in asymptomatic mandibular first molars. Using a crossover design, 100 subjects randomly received intraseptal injections of 1.4 mL of 4% articaine and 2% lidocaine, both with 1:100,000 epinephrine, at 2 separate appointments. Injections were given in the interdental papillae, mesial (0.7 mL) and distal (0.7 mL) to the first molar. An electric pulp tester was used to test for pulpal anesthesia. Pain of injection, postoperative pain, and pulse rate were also evaluated. Data were statistically analyzed. Anesthetic success rate for the mandibular first molar was 32% for articaine and 30% for lidocaine, with no statistically significant difference (p = .8689) between the two. No significant differences were found between formulations for pain of injection. The intraseptal injection did not cause a clinically meaningful increase in pulse rate. Postoperative pain decreased each day with no significant differences between formulations. In conclusion, a primary intraseptal injection does not achieve a high success rate of pulpal anesthesia in the mandibular first molar.