Peripherin is a type III intermediate filament protein detected in axonal spheroids associated with amyotrophic lateral sclerosis (ALS). The overexpression of peripherin induces degeneration of spinal motor neurons during aging in transgenic mice and in cultured neuronal cells derived from peripherin transgenic embryos. Here, we investigated whether peripherin is a contributor of pathogenesis in mice overexpressing a mutant superoxide dismutase 1 (SOD1(G37R)) gene linked to familial ALS. This was done by the generation and analysis of SOD1(G37R) mice that either overexpress a peripherin transgene (G37R;TgPer mice) or lack the endogenous peripherin gene (G37R;Per-/- mice). Surprisingly, upregulation or suppression of peripherin expression had no effects on disease onset, mortality, and loss of motor neurons in SOD1(G37R) mice. These results provide compelling evidence that peripherin is not a key contributor of motor neuron degeneration associated with toxicity of mutant SOD1.