Nuclear receptor interaction protein (NRIP) composes of 860 amino acids, includes 7 WD40 domains and 1 IQ motif. NRIP is a member of acetylcholine receptor (AChR) complex which plays an important role in the formation of neuromuscular junction (NMJ). Autoimmune deficiency is often associated with neuropathy. Myasthenia gravis (MG) is an autoimmune disease of NMJ. Previously, we characterized that NRIP autoantibody is found in myasthenia gravis and correlated with disease progression when anti-AChR autoantibody occurred. Amyotrophic lateral sclerosis (ALS) is a fetal neurodegenerative disease and progressive motoneuron loss leads to muscle atrophy and weakness. Here, to investigate the effect of anti-NRIP autoantibody in ALS patients; the existence of anti-NRIP autoantibody was found in 26 out of 87 ALS patients (29.9%). In limb-onset ALS patients, subjects having anti-NRIP autoantibody showed significantly more rapid disease progression than those without anti-NRIP autoantibody. Furthermore, there was significant correlation between high titer of anti-NRIP autoantibody and the speed of disease progression; especially in the limb-onset ALS. The survival rate was negatively associated with high titer of anti-NRIP autoantibody. The epitope of anti-NRIP autoantibody was mapped to IQ motif of NRIP using various NRIP mutant domains; and the IgG subclass of anti-NRIP autoantibody belonged to IgG1 and IgG3 subclasses. Like MG, anti-NRIP autoantibody is a newly identified ALS-related autoantibody, which positively correlates with the ALS disease progression. Hence, anti-NRIP autoantibody can be a diagnosis marker of ALS.