We studied the ability of anti-GM1 ganglioside antibodies to bind to GM1 in a lipid, "membrane-like" environment. Liposomes containing GM1 were synthesized to simulate this environment. We then compared the binding of anti-GM1 a autoantibodies to GM-1-liposomes and to purified GM1. Antibody binding was quantitated using enzyme-linked immunosorbent assay methodology. Our results showed a 250-fold variation in the ability of anti-GM1 antibodies to bind to GM1-liposomes. There was no correlation between GM-1-liposome binding and the carbohydrate specificities of the anti-GM1 antibodies. However, anti-GM1 antibodies from patients with amyotrophic lateral sclerosis (ALS) showed a 4 fold greater binding to GM1-liposomes than antibodies from patients with lower motor neuron (LMN) syndromes. We conclude that a lipid, presumably "membrane-like", environment may greatly influence the degree of anti-GM1 antibody binding to GM1. The low levels of anti-GM1 antibody binding to GM1-liposomes in patients with LMN syndromes may provide a diagnostic means for distinguishing these patients from those with ALS. Anti-GM1 antibodies from patients with ALS may bind especially well to neuronal membranes containing GM1 in vivo.