Mutations in superoxide dismutase 1 (SOD1) cause amyotrophic lateral sclerosis (ALS) in a subset of patients. Neurofilaments (NFs), the most abundant protein in motoneurons, may play a role in motoneuron degeneration. To investigate this role, we crossed transgenic mice expressing SOD1 mutant G93A (G93A mice) with mice overexpressing mouse neurofilament subunit H (H mice) or L (L mice). G93A mice overexpressing either NF-L or NF-H developed ALS later and survived longer than the G93A mice on a wild type background. These results illustrate a beneficial role of neurofilaments in ALS and call into question of several hypotheses regarding the role of neurofilaments in the development of ALS.