In order to define genetic, immunological and metabolic risk factors and markers associated with diabetic neuropathy (DN) 47 insulin-dependent diabetic patients with neuropathy were compared to 30 age-matched insulin-dependent diabetes mellitus (IDDM) patients without neuropathy. Patients with diabetic neuropathy more often had proliferative retinopathy and Albustix positive proteinuria than patients without neuropathy. Judged by haemoglobin A1 (HbA1) concentrations measured during the preceding two years glycaemic control was worse in patients with than without diabetic neuropathy. The frequency of HLA-antigens DR3, DR4, DR3/DR4, B8, and B15 were increased and those of DR2 and B7 decreased in the diabetic patients. The frequency of any of these HLA-antigens did not differ in patients with or without diabetic neuropathy. There were no significant differences in the frequencies of insulin antibodies or proliferative responses to insulin antigens between patients with or without diabetic neuropathy. However, patients who were HLA-DR3/DR4 heterozygotes and had diabetic neuropathy responded to insulin antigens more often by proliferation than DR3/DR4 positive patients without diabetic neuropathy. Thus poor glycaemic control is associated with an increased risk for diabetic neuropathy. Patients with DR3/DR4 heterozygocity and failing to respond to insulin antigens by proliferation seem to be less prone to develop diabetic neuropathy.