Kinetic study of degradation of two oral antidiabetics, gliclazide and glipizide, was performed using new HPLC method which was validated in terms of selectivity, sensitivity, linearity, precision and accuracy. The stress degradation was performed in 0.2 M HCl, 0.2 M NaOH as well as in acetate and phosphate buffers over the pH range 3.8–8.3 at 30 and 70°C. In strong acidic and alkaline media gliclazide was almost fully degraded while glipizide showed much higher stability. Generally, degradation processes of gliclazide and glipizide were observed as the first order reactions while the rates of decomposition for both drugs were smallest at pH 8.3. The samples of gliclazide and glipizide stressed in strong acid and alkali at 70°C were additionally analyzed using an LC/MS method and some products of decomposition were detected and identified. It was concluded that glipizide was more resistant to very high or very low pH and would have higher stability compared to gliclazide. Such comparisons have not been performed so far for these valuable drugs. Additional LC/MS study showed that during decomposition of sulfonylureas, different degradation pathways were possible.