Introduction: The sticky platelet syndrome (SPS) is a common cause of thrombosis. There are no prospective studies concerning treatment. Objective: To analyze changes in platelet hyperaggregability of patients with SPS who were given antiplatelet drugs and to assess its association with rethrombosis. Methods: A total of 55 patients with a history of thrombosis and SPS phenotype were prospectively studied before and after treatment with aspirin and/or clopidogrel. Results: Patients were followed for 1 to 129 months, median 13. Of 55 patients, 40 received aspirin, 13 received aspirin + clopidogrel, and 2 received only clopidogrel. The platelet aggregation response to adenosine diphosphate and epinephrine significantly diminished after treatment, and only 2 patients developed rethrombosis 52 and 129 months after starting therapy, with the freedom from rethrombosis rate of the patients being 96.4% at 129 months. Conclusion: Using antiplatelet drugs, the platelet hyperreactivity of patients with the SPS phenotype was reverted; and this translated into a substantial decrease in the rethrombosis rate.