Background It is widely supposed, but not well-demonstrated, that cumulative advances in standard care have reduced recurrent stroke and cardiovascular events in secondary prevention trials. Methods and Results Systematic search identified all randomized controlled trials (RCTs) of medical secondary stroke prevention therapies published from 1960 to 2009. RCTs narrowly focused on single stroke mechanisms, including atrial fibrillation, cervical carotid, and intracranial stenosis were excluded. From control arms of individual trials, we extracted data for baseline characteristics and annual event rates for recurrent stroke, fatal stroke, and major vascular events, and analyzed trends over time. 59 RCTs were identified, enrolling 66,157 patients in control arms. Over the 5 decade periods, annual event rates declined, per decade, for recurrent stroke by 0.996% (p=0.001), fatal stroke by 0.282% (p=0.003), and major vascular events by 1.331% (p=0.001). Multiple regression analyses identified increasing antithrombotics use and lower blood pressures as major contributors to the decline in recurrent stroke. For recurrent stroke, annual rates fell from 8.71% in trials launched in 1960s, through 6.10% in 1970s, 5.41% in 1980s, 4.04% in 1990s, to 4.98% in 2000s. The sample size required for a trial to have adequate power to detect a 20% reduction in recurrent stroke increased 2.2-fold during this period. Conclusions Recurrent stroke and vascular event rates have declined substantially over the last 5 decades, with improved blood pressure control and more frequent use of antiplatelet therapy as the leading causes. Considerably larger sample sizes are now needed to demonstrate incremental improvements in medical secondary prevention.