The fate of neurofilament (NF) proteins was examined in sections of nerves from rats that survived for 3 to 90 days following nerve transection, using anti-NF monoclonal antibodies and immunohistochemical techniques. The same methods were also applied to twenty-three human nerve biopsy specimens. Granular debris with NF immunoreactivity was observed in the rat nerves for up to 21 days after transection. Similar granular debris with NF protein immunoreactivity was observed in nerve biopsy specimens from patients with axonal degeneration. This change was most evident in specimens that demonstrated abundant ovoids in teased fiber preparations and in a patient with a recent traumatic nerve transection. Similar granular debris was not observed in normal rat or human nerves. We conclude that degenerating NF proteins have a distinctive granular appearance and that NF immunoreactivity can be demonstrated in NF breakdown products with immunohistochemical techniques for prolonged periods of time in rat and human nerves undergoing axonal degeneration. Immunohistochemical studies with anti-NF monoclonal antibodies offer a novel approach to the evaluation of human nerve biopsy specimens.