Stiff-man syndrome is a rare neurological disorder characterized by skeletal muscle rigidity and spasms in which detection of circulating anti-glutamic acid decarboxylase antibodies has suggested an autoimmune pathogenesis. To further define the role of autoimmunity in the pathogenesis, we studied anti-glutamic acid decarboxylase antibodies, as well as organ- and non-organ-specific autoantibodies in 13 patients with stiff-man syndrome and 127 patients with other neurological disorders. Thyrogastric antibodies were more frequent in patients with stiff-man syndrome (46%) than in those with other neurological disorders (12%) (p < 0.05). Non-organ-specific antibodies were found at a similar frequency in the patients with stiff-man syndrome (61%) and those with other neurological disorders (65%). Islet-cell autoantibodies and anti-glutamic acid decarboxylase antibodies were more common in stiff-man syndrome patients (38% and 31%) compared to the patients with other neurological disorders (6% and 3%, respectively; p < 0.001). With the exception of 1 patient in the other neurological disorders group, anti-glutamic acid decarboxylase antibodies were always associated with islet-cell autoantibodies. Four patients with stiff-man syndrome had an associated solid tumor: 3 of them had antibodies recognizing a 125/130-kd protein and not glutamic acid decarboxylase.(ABSTRACT TRUNCATED AT 250 WORDS)