Patients with transient ischemic attack and ischemic stroke have a high risk of recurrent stroke and death. While aspirin is accepted as standard therapy in these patients, recent trials demonstrate that a combination of aspirin and extended-release dipyridamole or clopidogrel is superior to aspirin monotherapy. Blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers may also reduce recurrent stroke. The ongoing Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial is designed to evaluate whether extended-release dipyridamole plus aspirin compared with clopidogrel, and whether telmisartan in addition to usual care, in individuals after a stroke, will reduce the risk of further strokes. PRoFESS is a multicenter, randomized, double-blind trial involving 695 sites from 35 countries or regions. The primary outcome for the trial is recurrent stroke, using a time-to-event analysis. Safety is evaluated by assessing the risk of major hemorrhagic and other serious adverse events. With over 20,000 patients randomized, and utilizing a 2 x 2 factorial design, PRoFESS is the largest stroke trial to investigate the prevention of recurrent stroke.