Human familial amyotrophic lateral sclerosis with an H46R mutant Cu/Zn superoxide dismutase (SOD1) gene is characterized by initial muscle weakness and atrophy in the legs and a very long-term clinical course (approximately 15 years). Transgenic mice with this mutation generated in our laboratory occasionally showed aggregates in the anterior horns and axonal degeneration in all white matter sections of the spinal cord on plastic sections at the presymptomatic stages (12 and 16 weeks old), although conventional staining revealed no pathologic changes. At the symptomatic stages (20 and 24 weeks), loss of anterior horn neurons was observed. On plastic sections, aggregates were frequently seen not only in the anterior horns but also in the posterior horns and in all sections of white matter. Degenerated fibers were observed in the anterior and posterior roots as well as in white matter. Electron and immunoelectron microscopic observation revealed human SOD1- and ubiquitin-positive aggregates consisting of intermediate filaments in the anterior horn even from an early presymptomatic stage. Thus, H46R mutant SOD1 transgenic mice are characterized by widespread pathologic changes of the spinal cord that extend beyond the motor system, including many aggregates lacking vacuoles. The close pathologic similarity makes this animal model suitable for the investigation of human familial amyotrophic lateral sclerosis with the mutation.