Background: Intraneural (intrafascicular) injection of various solutions can result in a mechanical injury to the fascicle(s). Additional injury can be expected when injectate has neurotoxic properties. In this study we examined the neurologic consequences of intraneurally injected lidocaine 2% and 0.9% NaCl. We postulated that intraneural injection of lidocaine 2% results in greater and longer-acting neurologic deficit in rats compared to intraneural injection of 0.9% NaCl. Methods and Materials: The study was conducted in accordance with the principles of laboratory animal care and was approved by the Laboratory Animal Care and Use Committee. Twenty four adult Wistar rats (300 g) both sexes were studied. After induction of general anesthesia (ether), the median nerve was exposed bilaterally. Under direct vision, a 27-gauge needle was placed either perineurally (n=24) or intraneurally (n=24), and 3 mL of preservative-free lidocaine 2% or 0.9% was injected using an automated infusion pump (3ml/min). Injection pressure data were acquired using an in-line manometer coupled to a computer via an analog-to-digital conversion board. After injection, the rats were awakened and subjected to serial neurologic examinations. Neurologic examination protocol was followed to determine grip strength and toe pinch reaction. Day 7 of the experiment, the animals were sacrificed and the neural tissue histologically examined. Results: Over the week following the procedure, all animals in both injection protocols (intraneural and perineural) initially lost and subsequently regained grip strength and paw pinch withdrawal reflex. Animals in the perineural group fully recovered grip strength and toe pinch score within 24-hours of surgery; the saline group showed more rapid recovery. In contrast, neither the lidocaine 2% or 0.9% saline intraneural group fully recovered a grip strength or toe pinch until the 7th or 4th day of recovery, respectively. There were no differences in the extent of neurologic impairment or speed of recovery between the saline and lidocaine 2% groups. Post-hoc comparisons of the four injection group by treatment condition effect at each testing interval post-surgery showed superior recovery in the perineural injected preparations at all intervals tested after hour 4 (p < 0.001). The average peak pressure for the intraneural injection group was 80.96 ± 20.94 kPa versus 21.63 ± 5.58 kPa for the perineural injection group (p < 0.0001). Histologic features of the injured tissues ranged from perineural ablation, cellular infiltration to destruction of neural architecture and axonal degeneration in intraneural preparations. No differences in this regard were found between lidocaine 2% and saline 0.9% groups. Conclusions: Intraneural injection of lidocaine 2% or 0.9% NaCl result in an indistinguishable neurologic deficit that is similar both in extent and duration. Intraneural injection is associated with significantly higher injection pressure as compared to the perineural injection. These results suggest that the main mechanism of neurologic injury resulting from an intraneural injection of lidocaine 2% may be a mechanical, injury to the fascicle(s), rather than a direct neurotoxicity.