Background Small subcortical strokes, also known as lacunar strokes, comprise more than 25% of brain infarcts, and the underlying vasculopathy is the most common cause of vascular cognitive impairment. How to optimally prevent stroke recurrence and cognitive decline in S3 patients is unclear. The aim of the Secondary Prevention of Small Subcortical Strokes study (Trial registration: NCT00059306) is to define strategies for reducing stroke recurrence, cognitive decline, and major vascular events. Methods Secondary Prevention of Small Subcortical Strokes is a randomised, multicentre clinical trial ( n=3000) being conducted in seven countries, and sponsored by the US NINDS/NIH. Patients with symptomatic small subcortical strokes in the six-months before and an eligible lesion on magnetic resonance imaging are simultaneously randomised, in a 2 × 2 factorial design, to antiplatelet therapy – 325 mg aspirin daily plus 75 mg clopidogrel daily, vs. 325 mg aspirin daily plus placebo, double-blind – and to one of two levels of systolic blood pressure targets –‘intensive’ (<130 mmHg) vs. ‘usual’ (130–149 mmHg). Participants are followed for an average of four-years. Time to recurrent stroke (ischaemic or haemorrhagic) is the primary outcome and will be analysed separately for each intervention. The secondary outcomes are the rate of cognitive decline and major vascular events. The primary and most secondary outcomes are adjudicated centrally by those unaware of treatment assignment. Conclusions Secondary Prevention of Small Subcortical Strokes will address several important clinical and scientific questions by testing two interventions in patients with recent magnetic resonance imaging-defined lacunar infarcts, which are likely due to small vessel disease. The results will inform the management of millions of patients with this common vascular disorder.