Eighteen patients with non-insulin-dependent (type 2) diabetes mellitus of normal body weight [body mass index (BMI) <25 kg/m2] without signs of autoimmunity [negative for islet cell antibodies (ICA)], with secondary failure of sulphonylureas, defined as persistent hyperglycaemia in spite of maximal doses of sulphonylureas, were evaluated for C-peptide release under basal conditions and 6 min after i.v. glucagon, for glycosylated haemoglobin (HbA1C), and for fasting and mean daily blood glucose levels. They entered a 6-month, single-blind study in which they were randomly assigned to one of three treatments: (1) insulin plus nicotinamide (group 1, 0.5 g, three tablets/day); (2) insulin plus placebo (group 2, 3 tablets/day); (3) current sulphonylureas plus nicotinamide (group 3, 0.5 g, three tablets/day). They were re-evaluated for C-peptide, HbA1C, and fasting and mean daily blood glucose levels after 6 months. Compared with group 2, C-peptide release increased in both groups 1 and 3, while HbA1C, fasting and mean daily blood glucose levels improved in the three groups to the same extent. With multiple regression analysis, nicotinamide administration was the only significant factor for the improvement of C-peptide release. These data indicate that nicotinamide improves C-peptide release in type 2 diabetic patients with secondary failure of sulphonylureas, leading to a metabolic control similar to patients treated with insulin.