INTRODUCTION: The diagnosis of many proximal lower limb mononeuropathies or lumbosacral plexopathies remains elusive despite thorough evaluation, including routine MRI and even, sural nerve biopsy. Empiric treatment (be it medical or surgical) is typically attempted with limited success for neurologic recovery. METHODS: In the past year, ten patients (7 men and 3 women) with an average age of 42 years [range, 16-76] with progressive non-compressive peroneal, tibial, sciatic neuropathies or lumbosacral plexopathies affecting 14 limbs were evaluated. Localization was established by physical examination and confirmed with electrodiagnostic studies. In addition, high resolution MR neurograms of the lumbosacral spine, pelvis and lower extremity were performed. Six patients had previous non-diagnostic distal cutaneous nerve biopsy (sural in 5 and superficial peroneal in 1). Targeted fascicular biopsy was then performed of the peroneal (1), tibial (2) or sciatic nerve (7). The biopsy site was selected based on the location of percussion tenderness and surgical accessibility, and correlated with the site of imaging abnormalities. The individual fascicle was selected by the pattern of maximal preoperative neurologic deficit, intraneural topography of the nerve, and the pathologic appearance observed at operation. RESULTS: In all patients, percussion of the affected nerve produced radiating paresthesias. This site correlated with signal abnormality and/or enlargement of the nerves demonstrated on MRI studies that were independently reviewed. These imaging abnormalities were often subtle. They were identified prospectively by a radiologist with expertise in peripheral nerve imaging, but were not usually appreciated by the initial reading by a general radiologist. In all cases, the proximal fascicular biopsy was informative for a specific pathologic alteration: lymphoma (1), sarcoidosis (1), perineurioma (2), inflammatory/immune suggesting vasculitis (2) and inflammatory/demyelinating (4). No neurologic worsening resulted from the fascicular biopsy. The MRI scans were useful in localizing these proximal limb nerve lesions, but were not by themselves diagnostic of the pathologic process. CONCLUSIONS: Targeted fascicular biopsy based on clinical and radiographic assessment is a useful technique for diagnosing proximal lower limb mononeuropathies or lumbosacral plexopathies. This technique when performed at a center specializing in peripheral nerve diseases can establish the diagnosis and be performed safely, and has therapeutic implications.