Circulating IgG antibodies to carbohydrate determinants on GQ1b ganglioside are found in the acute phase sera of patients with Miller Fisher syndrome, a variant of Guillain-Barré syndrome. Here we report that the IgG subclass distribution of the anti-GQ1b antibodies is mainly restricted to IgG1 and IgG3 antibodies, subclasses typically associated with a T cell-dependent immune response to protein antigens. This is highly unusual in that IgG responses to carbohydrate determinants are typically of the IgG2 subclass. Anti-GQ1b antibodies also have a limited ability to bind GQ1b in a membrane-like environment, particularly at body temperature. These data suggest that the antigen initiating the immune response in MFS is not likely GQ1b but an unidentified cross-reactive glycoprotein antigen(s). Similar results were obtained for anti-GM1 IgG antibodies in Guillain-Barré syndrome.