Antibodies against GD1a, GM1 and related gangliosides are frequently present in patients with the motor variant of Guillain–Barré syndrome (GBS), and their pathological role in this variant of GBS is now widely accepted. However, two basic issues related to anti‐ganglioside antibody‐mediated neural injury are not completely resolved: (i) some anti‐ganglioside antibodies can cross‐react with glycoproteins and therefore the nature of antigens targeted by these antibodies is not well established; and (ii) although pathological studies suggest that complement activation occurs in GBS, experimental data for the role of complement remain inconclusive. To address these issues, we developed and characterized a simple anti‐ganglioside antibody‐mediated cytotoxicity assay. Our results demonstrate first, that both GBS sera containing anti‐ganglioside antibodies and monoclonal anti‐ganglioside antibodies cause neuronal cell lysis by targeting specific cell surface gangliosides, and secondly, that this cell lysis is complement dependent. In this assay, the GD1a cell membrane pool appears to be more susceptible to anti‐ganglioside antibody‐mediated injury than the GM1 pool. Further, human intravenous immunoglobulin (IVIg), now a standard treatment for GBS, significantly decreased cytotoxicity in this assay. Our data indicate that the mechanisms of IVIg‐mediated protection in this assay include anti‐idiotypic antibodies and downregulation of complement activation. This simple cytotoxicity assay can potentially be used for screening of (i) pathogenic anti‐ganglioside antibodies in patients with immune‐mediated neuropathies; and (ii) new/experimental therapies to prevent anti‐ganglioside antibody‐mediated neural injury.