Objectives: To determine whether glycine receptor α1 subunit-specific autoantibodies (GlyRα1-IgG) occur in a broader spectrum of brainstem and spinal hyperexcitability disorders than the progressive encephalomyelitis with rigidity and myoclonus phenotype recognized to date, and to ascertain disease specificity. Design: Retrospective, case-control study. Settings: Mayo Clinic, Rochester, Minnesota, and University of Barcelona, Spain. Patients: Eighty-one patients with stiff-man syndrome phenotype, 80 neurologic control subjects, and 20 healthy control subjects. Intervention: Glycine receptor α1-transfected cells to test serum or cerebrospinal fluid from cases and control subjects. Main Outcome Measures: Frequency of GlyRα1- IgG positivity among stiff-man syndrome phenotype cases and control subjects. Comparison of GlyRα1-IgG seropositive and seronegative cases. Results: Seropositive cases (12% of cases) included 9 with stiff-man syndrome (4 classic; 5 variant; 66% were glutamic acid decarboxylase 65-IgG positive) and 1 with progressive encephalomyelitis with rigidity and myoclonus. Immunotherapy responses were noted more frequently in GlyRα1-IgG-positive cases (6 of 7 improved) than in seronegative cases (7 of 25 improved; P=.02). The single seropositive control patient had steroidresponsive vision loss and optic atrophy with inflammatory cerebrospinal fluid. Conclusions: Glycine receptor α1-IgG aids identification of autoimmune brainstem/spinal cord hyperexcitability disorders and may extend to the glycinergic visual system.