Antiplatelets, antihypertensives, and statins might reduce the severity of the event or improve outcome in patients who, despite prior medical treatment, have a stroke. We evaluated, in patients who had an ischemic stroke, the effect, on stroke severity and outcome, of prior treatment with antiplatelets, antihypertensives, and statins, used either alone or in a three-drug combination. Stroke in Italy and Related Impact on Outcome (SIRIO) was a prospective, nationwide, multicenter, hospital-based, observational study that included patients aged.18 years with acute ischemic stroke. We studied 2,529 acute ischemic stroke patients from the SIRIO population: 887 were antiplatelet users, 1,497 antihypertensive users, 231 statin users, and 138 three-drug combination users prior to the index event. The adjusted logistic regression analysis showed an association between prior treatment with statins and good functional outcome at discharge, while prior treatment with antiplatelets, antihypertensives or the three-drug combination did not influence severity or outcome. The absolute probability of a good functional outcome was 46.3% (95% CI: 40.3%-53.2%) in statin users and 36.7% (95% CI: 34.7%-38.7%) in non-users of statins; the absolute risk difference was 9.6% (95% CI: 2.9%-16.4%; p=0.004). Prior treatment with antiplatelets, antihypertensives, or the three-drug combination did not influence stroke severity or outcome, while prior treatment with statins did not influence stroke severity but was associated with a better functional outcome.