We made serial measurements of the platelet intracellular free calcium concentration in 167 patients with non-insulin-dependent diabetes mellitus (77 males and 90 females) over a two-year period, and investigated the relationship between this parameter and diabetic angiopathy. We measured both the basal and thrombin-stimulated platelet free calcium concentrations using fura-2/AM as a fluorescent indicator. The patients were grouped according to the severity of nephropathy, retinopathy, and hypertension and their hemoglobin A1c levels. The basal platelet calcium level of the diabetic patients was higher than that of a healthy control group. There were high levels in the patients with mild nephropathy and retinopathy, but low levels in those with severe disease, and the platelet calcium level reflected the degree of progression of diabetic angiopathy. Stimulated platelet calcium varied with the progression of nephropathy, being highest in early nephropathy and lowest after proteinuria developed. Our findings suggested that abnormalities of calcium handling may be related to the onset of diabetic vascular complications, especially diabetic nephropathy.