The purpose of this prospective, randomized, single-blind study was to determine the anesthetic efficacy of lidocaine with epinephrine compared to lidocaine with epinephrine plus 0.5 M mannitol in inferior alveolar nerve (IAN) blocks. Forty subjects randomly received an IAN block in 3 separate appointments spaced at least 1 week apart using the following formulations: a 1.8 mL solution of 36 mg lidocaine with 18 µg epinephrine (control solution); a 2.84 mL solution of 36 mg lidocaine with 18 µg epinephrine (1.80 mL) plus 0.5 M mannitol (1.04 mL); and a 5 mL solution of 63.6 mg lidocaine with 32 µg epinephrine (3.18 mL) plus 0.5 M mannitol (1.82 mL). Mandibular teeth were blindly electric pulp tested at 4-minute cycles for 60 minutes postinjection. No response from the subject to the maximum output (80 reading) of the pulp tester was used as the criterion for pulpal anesthesia. Mean percent total pulpal anesthesia was defined as the total of all the times of pulpal anesthesia (80 readings) over the 60 minutes. Pain of solution deposition and postoperative pain were also measured. The results demonstrated that 2.84 mL of lidocaine with epinephrine plus 0.5 M mannitol was significantly better than 1.8 mL of lidocaine with epinephrine for the molars and premolars. The 5 mL of lidocaine with epinephrine plus 0.5 M mannitol was statistically better than 1.8 mL of lidocaine with epinephrine and 2.84 mL of lidocaine with epinephrine plus 0.5 M mannitol for all teeth except the central incisor. Solution deposition pain and postoperative pain were not statistically different among the mannitol formulations and the lidocaine formulation without mannitol. We concluded that adding 0.5 M mannitol to lidocaine with epinephrine formulations significantly improved effectiveness in achieving a greater percentage of total pulpal anesthesia compared with a lidocaine formulation without mannitol for IAN block.