In clinical practice of hypoglycemic therapy of diabetes mellitus the problem of the optimal selection of oral hypoglycemic agent, corresponding to the individual patterns of regulatory and metabolic disturbances is of primary importance. The individual, pathophysiological basis should be met as much as possible by the pharmacodynamic properties of the selected, hypoglycemic drug. For this reason group of 23 diabetics type II underwent a prolonged, open trial of controlled pharmacotherapy with 4 sulphonylurea derivatives. Pertinent clinical and metabolic parameters were assessed before, during and after planned periods of therapy with Tolbutamide or Chlorpropamide to Gliclazide and Gliclazide to Glibenclamide. In the same time the levels of serum insulin fasting and after breakfast were determined. Also the comparative efficacy of the exchange of the drug in a subgroup of diabetics with fasting glycemia below and above 160 mg% was assessed. It was shown, that the change of Tolbutamide or Chlorpropamide to Gliclazide or Glibenclamide improved the therapeutical effectiveness in general. The individual responses to such a change were however individually differentiated. The change of Tolbutamide or Chlorpropamide to Gliclazide increased the therapeutical efficacy only in these patients, in whom such a change was associated with an increase of prandial, reactive serum insulin level (IRI). In practice they were patients with the fasting glycemia lower than 160 mg%. In patients with fasting glycemia higher than 160 mg% the change of oral compounds under study was not connected with an increase of prandial serum insulin. The metabolic parameters have not improved either. Perhaps they were patients with diabetes mellitus type II, who should be primarily qualified to insulin.