The aim of this study was to investigate the modifying effect of diabetes on thein vitroserum binding of gliclazide at therapeutic concentrations, and to try to determine the role of albumin glycation. Sera were obtained from 20 patients with diabetes and 20 matched nondiabetic controls. Gliclazide was addedin vitroat a therapeutic concentration (5 mg/L). After equilibrium dialysis, gliclazide was assayed by high-performance liquid chromatography, while glycated albumin was assayed by affinity chromatography and laser-nephelemetry. The mean binding of gliclazide was lower in diabetics (82.6 ± 4.1%) than in controls (88.8 ± 4.8%) [p<0.001]. No correlation was observed between gliclazide binding and the percentage of albumin glycation. Sera were also obtained from the same diabetic patients 3 months later. There was no correlation between variation of glycated albumin and variation of gliclazide binding over 3 months. The protein binding of gliclazide was lower in diabetics than in matched controls. Furthermore, the decreased binding was not dependent upon the level of albumin glycation, and did not disappear when chronic hyperglycaemia was corrected.