The purpose of this prospective, randomized study was to compare the degree of pulpal anesthesia obtained in vital, asymptomatic teeth using 1.8 mL of 1% diphenhydramine with 1:100,000 epinephrine, 1.8 mL of 2% lidocaine with 1:100,000 epinephrine, and 3.6 mL of 2% lidocaine with 1:100,000 epinephrine combined with 1% diphenhydramine with 1:100,000 epinephrine in inferior alveolar nerve blocks. We also studied injection and postinjection pain. An electric pulp tester was used to test for anesthesia, in 4-minute cycles for 60 minutes, of the second molars through the central incisor. Anesthesia was considered successful when two consecutive 80 readings were obtained within 15 minutes and the 80 reading was continuously sustained through the 60th minute. Using the lidocaine solution, successful pulpal anesthesia ranged from 12% to 84%. For the combined lidocaine/diphenhydramine solution, successful pulpal anesthesia ranged from 4% to 60%. The diphenhydramine solution was irritating on injection and postinjection and resulted in a very low level of anesthetic success. We concluded that a 1% diphenhydramine solution should be used cautiously for the inferior alveolar nerve block. The combination lidocaine/diphenhydramine solution was irritating postinjection and was not as effective as a lidocaine solution for pulpal anesthesia.