OVERALL AIM The aim of the Secondary Prevention of Small Subcortical Strokes (SPS3) project is to define efficacious therapies for prevention of recurrent stroke and cognitive decline in patients with small subcortical strokes (S3) (a.k.a. lacunar infarcts). Nearly two million survivors of S3 in U.S. are at high risk for recurrent stroke and for developing vascular dementia. Additionally, "asymptomatic" (more accurately termed "subclinical") S3 are present in about 20% of people over age 65. While S3 can be caused by many types of cerebrovascular disorders, most are due to intracranial cerebral small artery disease. Optimal antiplatelet therapy and antihypertensive management of S3 patients to reduce stroke recurrence and cognitive decline has not been defined and is likely to yield important health benefits. Although MRI-defined symptomatic S3 in the absence of surgically amenable cervical carotid stenosis and major-risk cardioembolic sources is the index event for participation in SPS3 and recurrent stroke is the primary outcome, the goals of SPS3 are broader in scope and include assessment and prevention of vascular dementia. No previous clinical trials have addressed these important issues specifically in S3 patients. SPS3 will define optimal treatment to prevent recurrent stroke and cognitive decline for S3 patients without an indication for endarterectomy or anticoagulation. S3s are particularly frequent in Hispanics, in whom they are one of the most common stroke subtypes. Whether the prognosis of S3 and the benefits of aggressive blood pressure control and of enhanced antiplatelet therapy are importantly different in Hispanic are also not known, and these issues will be addressed by SPS3. SPS3 seeks to efficiently address several important clinical and scientific questions through two simultaneous clinical trials coupled with careful, prospective analysis of features potentially influencing prognosis and response to interventions. Since hypertension is the most prevalent and powerful risk factor for S3, and antiplatelet therapy is the standard of care for secondary prevention, definition of the efficacy and safety of blood pressure control and antiplatelet therapy should optimally be tested together. SPECIFIC AIM: To define efficacious therapies for prevention of stroke recurrence and cognitive de-cline in patients with symptomatic S3. The core of SPS3 consists of two randomized clinical trials involving 2500 participants with symptomatic S3 randomized to two interventions in a factorial design. Primary Aims: A) To determine whether combination antiplatelet therapy consisting of aspirin (325 mg/d) plus clopidogrel (75 mg/d) is superior to aspirin (325 mg/d) for reducing stroke recurrence (the primary endpoint), cognitive decline and major vascular events. B) To determine whether "intensive" blood pressure lowering to a specific target range is superior to "usual" hypertension management for reducing recurrent stroke, cognitive decline and major vascular events. Secondary Aim: To compare the differences in absolute benefit of combination antiplatelet therapy vs. aspirin and of "intensive" blood pressure lowering vs. "usual control" between Hispanic participants vs. non-Hispanic white participants. Rationale'. Hispanics will have larger benefits (absolute risk reductions) from combination antiplatelet therapy and from "intensive" blood pressure control for prevention of stroke recurrence than non-Hispanic whites, based on their higher rate of recurrent stroke. In addition, the inclusion of 20% of Hispanic participants will serve to characterize S3 in this population, including stroke recurrence rate and risk factors, rate and risk factors for cognitive decline, response to antiplatelet intervention, and response to blood pressure control intervention. IMPORTANCE/RELEVANCE OF SPS3. At least 200,000 S3s occur annually in the U.S., with nearly two million S3 survivors at high risk for recurrent stroke and vascular dementia. It remains unclear how to optimally prevent stroke recurrence and cognitive impairment in S3 survivors. No clinical trials have specifically focused on this important, common stroke subtype. No secondary stroke prevention study has tested different target levels of blood pressure control in stroke survivors, despite the importance of hypertension as the most common independent risk factor for stroke, and particularly for S3. No previous stroke study has focused on Hispanics;S3 is one the most frequent stroke subtype among this fastest growing U.S. minority. Additional millions of Americans have "subclinical" S3 and cognitive impairment associated with cerebral small artery disease;the results of SPS3 will likely impact their management as well.