Hepatitis C virus (HCV)-associated neuropathy is usually associated with mixed cryoglobulinemia (MC) and vasculitis. MC may contain viral RNA, and tissues showing vasculitis may contain intracellular HCV. Local HCV replication remains to be evidenced. To delineate the spectrum of HCV-associated neuropathy and to assess the presence of HCV in nerve and muscle tissues. Thirty consecutive HCV-infected patients with peripheral neuropathy were included. Genomic and replicative strands of HCV RNA were detected in both nerve and muscle biopsy samples using distinctive reverse transcription nested PCR. Neuropathy was consistent with distal axonal polyneuropathy (DPN) in 25 of 30 patients, mononeuropathy multiplex (MM) in 3 of 30, and demyelinating polyneuropathy in 2 of 30. Pain was present in 18 of 30 patients and MC in 16 of 30. Biopsy showed inflammatory vascular lesions in 26 of 30 patients (87%), including necrotizing arteritis (6/30), small-vessel vasculitis (12/30) of either the lymphocytic (9/12) or the leukocytoclastic (3/12) type, and perivascular inflammatory infiltrates (8/30). All patients with necrotizing arteritis had DPN and positive MC detection. Both pain (p < 0.03) and positive MC detection (p < 0.01) were associated with the presence of vasculitis. Positive-strand genomic HCV RNA was detected in tissues of 10 of 30 patients (muscle 9, nerve 3). In contrast, negative-strand replicative RNA was never detected. Genomic RNA was found in nerve tissue samples showing vasculitis (necrotizing arteritis 2, small-vessel lymphocytic vasculitis 1). Painful DPN associated with MC and neuromuscular vasculitis is the most frequent type of HCV neuropathy. The usual detection of MC and the lack of local HCV replication indicate that HCV neuropathy results from virus-triggered immune-mediated mechanisms rather than direct nerve infection and in situ replication.