We examined the pancreases from three nondiabetic, autoimmune, polyendocrine patients with islet cell antibodies (ICAs) and glutamic acid decarboxylase (GAD) antibodies who died without developing insulin-dependent diabetes mellitus (IDDM). All three patients had the β-selective GAD-specific ICA subtype and antibodies to the GAD-derived 50 kD tryptic fragment. None had whole islet ICA or antibodies to the non-GAD-derived 37k islet antigen, which appear to be more closely associated with IDDM than antibodies to GAD. The three patients also were negative for insulin autoantibodies. Islets within pancreas from patients 1 and 2 appeared well preserved as assessed by hematoxylin and eosin staining. In these two patients, insulin content, as assessed by indirect immunofluorescence on cryostat sections, was normal. Patient 3 had a prolonged postmortem time, and the islet insulin content was reduced slightly. In all three pancreases, no evidence was found of increased human leukocyte antigen class I or de novo class II molecule expression on islet cells, and islet infiltration by T- or B-cells or macrophages was not detected. Islet capillary endothelial cells did not show signs of hypertrophy. No immunoglobulin or complement deposition within or around islets was found. These data indicate that humoral GAD autoimmunity does not necessarily associate with visible β-cell damage.