On the western Pacific island of Guam, parkinsonism, dementia, and amyotrophic lateral sclerosis are highly prevalent but the cause is not known. To assess the possibility that the pathologic process extends beyond the nervous system, we studied patients with Guamanian neurodegenerative disease (N = 16) and Guamanian Chamorro control subjects (N = 16) in the Clinical Research Center of the Mayo Clinic, Rochester, MN. The principal abnormalities found in those with neurodegenerative disease included diabetes mellitus in 44%, elevated levels of serum immunoglobulin A (IgA) in 50%, and elevated IgG in 44%. The mean serum IgM level in the patient group was significantly lower than in the control group. Diabetes mellitus and elevated IgA and IgG levels were also present in 31% of neurologically normal Guamanian subjects. Some of these control subjects, however, probably have preclinical neurodegenerative disease, as found in previously published postmortem studies. Extensive serologic testing did not reveal any consistent profile of autoimmunity. Other blood and urine studies failed to identify hematologic, nutritional, renal, hepatic, or metabolic abnormalities that distinguished patients. Whether diabetes mellitus or abnormalities of immune regulation share common etiopathology with Guamanian neurodegenerative disease deserves further study.