BACKGROUND The pathogenesis of secondary failure to hypoglycemic agents is heterogeneous. Some patients are true insulin dependent diabetics with a slow autoimmune disease suggested by their positive islet cell antibodies. Others, have an increased insulin resistance. OBJECTIVE To assess the frequency of positive islet cell antibodies in diabetic patients with secondary failure to oral hypoglycemic agents. METHODS Thirty one diabetics, 16 with recent (less than six months) secondary failure and 15 with metabolically stable non insulin dependent diabetes were studied. All patients were older than 25 years old and had a body mass index of less than 30 kg/m2. C peptide levels before and at 5, 15 and 30 min after IV glucagon, islet cell antibodies using the Poly Human IgG peroxidase method and insulin sensitivity and secretion (estimated by the Homeostasis Model Assessment) were measured. RESULTS Patients with secondary failure had lower C peptide levels, compared to subjects with stable diabetes (basal: 1.5 +/- 0.2 and 2.8 +/- 0.2 ng/ml; 5 min: 2.4 +/- 0.3 and 5.5 +/- 0.5 ng/ml; 15 min: 1.9 +/- 0.3 and 4.0 +/- 0.6 ng/ml; 30 min: 1.6 +/- 0.3 and 3.4 +/- 0.5 ng/ml). Beta cell activity was 20.6 +/- 4.3% in patients with secondary failure and 92.2 +/- 9% in stable diabetics (p < 0.01). Insulin sensitivity was similar in both groups (48.6 +/- 6 and 42.8 +/- 3.5% respectively). Three patients with secondary failure and none with stable diabetes had positive islet cell antibodies. When comparing patients with secondary failure and positive antibodies and subjects with secondary failure and negative antibodies, the former had non significantly lower age, BMI and C peptide levels. CONCLUSIONS Some diabetic patients with secondary failure have positive islet cell antibodies. They should be measured in these patients to start insulin treatment precociously.