Thirty-five non-insulin-dependent diabetic subjects were divided into two groups, according to therapeutical approach. The first group consisted of 17 diabetics receiving sulfonylureas and maintaining a satisfactory metabolic control. The second group included 18 patients who were transferred from sulfonylureas to insulin treatment, i.e. patients developing secondary failure to sulfonylurea drugs. We established that the patients with secondary failure to sulfonylurea drugs show a significantly lower B-cell secretory response following stimulation with i.v. tolbutamide, a significantly lower peripheral insulin sensitivity by euglycemic hyperinsulinemic clamp, and an increased frequency of HLAB21 and HLADR1 antigens. This latter study was performed in 42 patients. We thus conclude that in these patients diabetes mellitus may be considered as a separate form of the disease, which needs reevaluation of the criteria concerning therapeutical approach, prognosis, and evolution.