The purpose of this prospective, randomized, single-blind study was to determine the anesthetic efficacy of 127.2 mg lidocaine with 50 μg epinephrine compared to 127.2 mg lidocaine with 50 μg epinephrine plus 0.5 M mannitol in inferior alveolar nerve (IAN) blocks. Forty subjects randomly received 2 IAN blocks consisting of a 3.18 mL formulation of 127.2 mg lidocaine with 50 μg epinephrine and a 5 mL formulation of 127.2 mg lidocaine with 50 μg epinephrine (3.18 mL) plus 0.5 M mannitol (1.82 mL) in 2 separate appointments spaced at least 1 week apart. Mandibular anterior and posterior teeth were blindly electric pulp tested at 4-minute cycles for 60 minutes postinjection. Pain of solution deposition and postoperative pain were also measured. No response from the subject to the maximum output (80 reading) of the pulp tester was used as the criterion for pulpal anesthesia. Total percent pulpal anesthesia was defined as the total of all the times of pulpal anesthesia (80 readings) over the 60 minutes. One hundred percent of the subjects had profound lip numbness with both inferior alveolar nerve blocks. The results demonstrated that a 5 mL formulation of 127.2 mg lidocaine with 50 μg epinephrine plus 0.5 M mannitol was significantly better than the 3.18 mL formulation of 127.2 mg lidocaine with 50 μg epinephrine for all teeth. Solution deposition pain and postoperative pain were not statistically different between the lidocaine/mannitol formulation and the lidocaine formulation without mannitol. We concluded that adding 0.5 M mannitol to a lidocaine with epinephrine formulation was significantly more effective in achieving a greater percentage of total pulpal anesthesia than a lidocaine formulation without mannitol.