Platelets play a central role in the pathogenesis of coronary artery disease (CAD). Mean platelet volume (MPV) is an indicator of platelet activation, and has been demonstrated to be correlated with platelet reactivity. Diabetic patients have been shown to have larger MPV, that may contribute to higher platelet reactivity and atherothrombotic complications observed in these patients. Therefore, the aim of the current study was to investigate whether MPV is associated with platelet reactivity and the extent of CAD among diabetic patients. We performed a cohort study including 1016 consecutive diabetic patients undergoing coronary angiography at the University Hospital ‘Maggiore della Carita’, Novara, Italy. CAD is defined as stenosis above 50% in at least one coronary vessel at coronary angiography. Platelet reactivity was evaluated in 50 diabetic patients without history of CAD and who were free (in the past month) from medications which may affect platelet aggregation. Platelet aggregation was evaluated by light transmission aggregometry after stimulation with 1 μg/ml collagen type I. We additionally evaluated platelet surface expression of P-selectin after stimulation with U46619 (a stable synthetic analogue of the prostaglandin PGH2) and plasma concentration of thromboxane B2 (TxB2). Patients were grouped according to tertile values of MPV (<10.6 fl, group 1; 10.6–11.3 fl, group 2; >11.4 fl, group 3). MPV was associated with age (P = 0.011), baseline fasting glucose (P = 0.044), glycosylated haemoglobin (P = 0.005), creatinine (P = 0.052) and haemoglobin (P = 0.003), but inversely related to platelet count (P < 0.001) and triglycerides (P = 0.031). Larger MPV was associated with therapy with statins (P = 0.012) and diuretics (P = 0.021). CAD was observed in 826 patients (81.3%). MPV was not associated with the prevalence of CAD [odds ratio (OR), 0.85 (0.7–1.03), P = 0.11]. The results were confirmed in terms of severe CAD [OR, 1.03 (0.88–1.21), P = 0.7]. The absence of any significant relationship between MPV and CAD was confirmed after correction for baseline confounding factors [OR, 0.9 (0.75–1.08), P = 0.19]. Finally, MPV was not related to platelet reactivity. This is the first study showing that in diabetic patients MPV is not related to platelet reactivity and the prevalence and extent of CAD. Therefore, MPV may not be considered a risk factor for CAD among diabetic patients.