One of the most serious complications of mechanical valves is obstructive prosthetic valve thrombosis (OPVT or "stuck valve"). Some patients develop OPVT despite an international normalized ratio (INR) in the therapeutic recommended range. We hypothesized that patients who develop OPVT have hyper-reactive platelets. We, therefore, examined platelet reactivity in patients who developed OPVT, despite a therapeutic or near-therapeutic INR, compared with a matched control group. We compared platelet reactivity between patients who had had an OPVT episode, despite a therapeutic or near-therapeutic INR (n = 18), and a matched group of patients with mechanical valves who did not develop this complication (n = 18) from 1996 to 2007. Platelet reactivity was evaluated by platelet aggregation in response to various agonists, platelet deposition under flow conditions in the Impact-R system, and plasma levels of platelet activation markers (soluble CD40 ligand and P-selectin). In the OPVT group, the average INR during the index episode was 3.1 +/- 1.5, and 44.6 +/- 40 months had elapsed from the index episode to the present study. Both groups were matched for gender, age +/-10 years, valve position and type, active smoking, and diabetes. Patients with an OPVT history had a greater aggregation in response to collagen (p = 0.05), greater platelet deposition in the Impact-R system (p = 0.01), and tended to have higher levels of soluble P-selection and soluble CD40 ligand (p = 0.07) than their control counterparts. In conclusion, patients with a history of OPVT appear to have increased platelet reactivity, which might contribute to an increased risk of thrombotic complications. These patients would, therefore, likely benefit from the addition of antiplatelet therapy to their standard anticoagulant treatment.