Background and Purpose— Although secondary medical prevention strategies in patients with stroke are well established, only sparse data exist regarding their effectiveness in routine care. We examined the effectiveness in a nationwide, population-based follow-up study. Methods— Using data from the Danish National Indicator Project (DNIP), 28 612 patients hospitalized for ischemic stroke in 2003 to 2006 were identified. Information on drug use and outcomes was by individual-level record linkage with national medical databases. Hazard ratios were computed for death, myocardial infarction, and recurrent stroke according to drug use after hospital discharge. Results— Treatment with antiplatelets, oral anticoagulants, antihypertensives, or statins was associated with a lower risk of the combined end point of death, myocardial infarction, or recurrent stroke during a mean follow-up period of 2.7 years (adjusted hazard ratios [HRs] from 0.44 [95% CI, 0.39–0.49] to 0.94 [95% CI, 0.89–0.99]). All drug classes were associated with lower risk of death (adjusted HRs from 0.36 [95% CI, 0.32–0.41] to 0.85 [95% CI, 0.80–0.90]), with oral anticoagulant treatment in patients with atrial fibrillation being particularly effective in elderly women (>80 years; adjusted HR, 0.35; 95% CI, 0.28–0.45). Oral anticoagulant treatment was associated with a lower risk of recurrent stroke (adjusted HR, 0.58; 95% CI, 0.47–0.73), and statins were associated with a lower risk of myocardial infarction (adjusted HR, 0.84; 95% CI, 0.73–0.97) and recurrent stroke (adjusted HR, 0.86; 95% CI, 0.79–0.92). Conclusions— Secondary medical prophylaxis after ischemic stroke was associated with improved outcome in routine settings. Although these findings are of an observational nature, they tend to support the results from previous randomized trials.