Introduction: The prevalence and characteristics of agrin and low‐density lipoprotein–related receptor protein 4 (LRP4) antibody‐positive amyotrophic lateral sclerosis (ALS) patients were studied. Methods: We tested 82 ALS patients and 59 controls for agrin and LRP4 antibodies using enzyme‐linked immunoassay (ELISA). Results: We found that 13.8% of ALS patients had agrin antibodies, and 9.8% had LRP4 antibodies. Women with ALS are twice as likely as men to have antibodies. Agrin‐positive ALS patients are younger than agrin‐negative ALS patients. Conclusions: Antibodies to agrin and LRP4 are found in ALS patients. It must be determined whether these antibodies are pathogenic. Because antibody‐positive patients have upper as well as lower motor neuron findings, the antibodies' effects cannot be explained solely by their actions at the neuromuscular junction. A breakdown in interneuronal signaling may be the cause of ALS. Further research is needed to resolve this question. Muscle Nerve, 2016 Muscle Nerve 55: 430–432, 2017