'Secondary failure' of oral hypoglycemics, in non-insulin dependent diabetics, has been attributed to dietary non-compliance, inadequate drug dosage, metabolic stress, or true drug failure. Progressive loss of beta cell function is a suggested mechanism for true drug failure but on the basis of little documented evidence. In view of this, we have measured basal and glucagon-stimulated C-peptide levels, human leukocyte antigen (HLA) types, and islet cell antibodies in 20 non-insulin dependent diabetics with 'secondary failure' of oral agents. There were 16 females and four males with a mean ideal body weight of 1.30 units and mean duration of diabetes of 9.5 years. Fasting insulin (mean +/- SD: 15.1 +/- 10.6 mU/l) and fasting C-peptide (2.3 +/- 1.2 micrograms/l) were normal or slightly elevated in all but one patient. Mean C-peptide increased from 2.3 +/- 1.2 micrograms/l to 3.5 +/- 2.2 micrograms/l (152% over basal) 6 minutes after 1 mg i.v. glucagon. In 15 patients the C-peptide response was greater than 130% of basal. Islet cell cytoplasmic antibodies were detected in only two patients. The distribution of HLA types was not significantly different from a control population, with no increase in DR3 or DR4. Thus, absolute insulin deficiency is uncommon in non-insulin dependent diabetics with 'secondary failure' of oral hypoglycemic agents and such patients do not exhibit the immuno-genetic markers of insulin-dependent diabetes.