Statins reduce coronary heart disease risk by altering blood lipids and other mechanisms. One of the possible other mechanisms is through an effect on thrombosis. We assessed the effect of simvastatin 80 mg daily versus placebo given in a single blind crossover fashion on platelet size in response to standard ex vivo stimuli, a surrogate for platelet activation, in 12 subjects with type 2 diabetes and mixed dyslipidemia. Exposure to collagen, cold, and heat caused the expected changes in platelet volume. Contrary to our expectations, ex vivo platelet size during collagen and cold exposure increased by 2.6 and 1.7%, respectively (P < 0.05), during simvastatin treatment as opposed to the placebo period. We conclude that some of the effects of high dose simvastatin therapy on platelets may not necessarily be anti-atherogenic.