<i>Background:</i> The extent and implications of age- and sex-related differences in prophylaxis following ischemic stroke are unknown. We examined differences in the use of medical prophylaxis across age and sex groups in stroke patients after hospital discharge in Denmark and estimated the possible impact on age- and sex-related differences in mortality. <i>Methods:</i> A nationwide population-based follow-up study was conducted involving 28,634 patients hospitalized for ischemic stroke in 2003–2006 who survived 30 days after discharge. The proportion of patients who filled prescriptions for cardiovascular drugs within 0–6 and 12–18 months after discharge was determined. Mortality rates were compared across age and sex groups with and without controlling for use of medical prophylaxis. <i>Results:</i> Increasing age was associated with lower prophylaxis. Adjusted odds ratios for the use of a combination of a platelet inhibitor, an antihypertensive and a statin were 0.45 [95% confidence interval (CI): 0.38–0.54] and 0.52 (95% CI: 0.43–0.62) for men and women >80 years, respectively, compared with men ≤65 years. No systematic sex-related differences were identified. Continued drug use ranged from 66.1 to 91.9% for different drugs 12–18 months after discharge, with the lowest rate of continued use found among patients >80 years. Controlling for use of medical prophylaxis was associated with lower mortality rate ratios for elderly compared with younger patients. <i>Conclusions:</i> Continuous efforts are warranted to ensure implementation of evidence-based secondary prophylaxis among elderly patients with ischemic stroke.