Glucose (10-50 mM) added to samples of citrated whole blood increased the spontaneous platelet aggregation (SPA) that was observed upon stirring the samples, in a dose-dependent but time-independent manner. EDTA prevented and also reversed the SPA that occurred in the presence of glucose. Galactose, fructose and 2-deoxyglucose, but not sorbitol and sucrose, had effects on SPA similar to those of glucose. The effect of glucose on SPA in whole blood could not be specifically inhibited by tetramethylene glutaric acid (an inhibitor of aldose reductase). SPA was not affected by pentoxifylline, but was markedly reduced by chlorpromazine. We previously found that glucose, galactose, fructose and 2-deoxyglucose, but not sorbitol and sucrose, render red blood cells more fragile, and the results obtained in the present study provide further evidence that glucose as well as other reducing sugars potentiate SPA in whole blood by liberating ADP or other aggregating material from red blood cells.