Recent clinical and laboratory observations support a potential role for the platelet FcgammaRIIA receptor (FcR) in collagen-mediated platelet activation associated with arterial thrombosis. Stable age- and sex-independent variation in receptor expression exists. Flow cytometry showed that 100 diabetes patients had increased mean platelet FcR expression levels compared with 201 non-diabetes patients (P < 0.001). Aggregation studies following FcR cross-linking supported a receptor role in increased activation of diabetes platelets after collagen stimulation (P = 0.018). Immunoprecipitation of collagen-stimulated and FcR-crosslinked platelets demonstrated enhanced levels of tyrosine-phosphorylated Syk in diabetic platelets. Increased platelet FcR-mediated sensitivity to collagen may contribute to cardiovascular morbidity and mortality in diabetes.