SYNOPSIS We describe 20 patients with migraine headaches and/or migraine equivalents who had positive antinuclear antibodies (ANA) on routine laboratory screening: 17 of the 20 (85%) had elevated anti‐smooth muscle antibodies (ASMA) that were cytotoxic on Cr51 studies. No patient met criteria for defined autoimmune disorders and the remainder of an extensive autoantibody screen was unremarkable. Details of the clinical features and immunology of these patients are presented. The cytotoxicity of the ASMA suggests that they are capable of producing tissue damage and inflammation and could play a pathogenic role in the production of vascular headaches and/or central nervous system symptoms in these patients.