BACKGROUND Takotsubo syndrome is an increasingly common cardiac emergency with no known evidence-based treatment. OBJECTIVES The purpose of this study was to investigate cardiovascular mortality and medication use after takotsubo syndrome. METHODS In a case-control study, all patients with takotsubo syndrome in Scotland between 2010 and 2017 (n ¼ 620) were age, sex, and geographically matched to individuals in the general population (1:4, n ¼ 2,480) and contemporaneous patients with acute myocardial infarction (1:1, n ¼ 620). Electronic health record data linkage of mortality outcomes and drug prescribing were analyzed using Cox proportional hazard regression models. RESULTS Of the 3,720 study participants (mean age, 66 years; 91% women), 153 (25%) patients with takotsubo syndrome died over the median of 5.5 years follow-up. This exceeded mortality rates in the general population (N ¼ 374 [15%]; HR: 1.78 [95% CI: 1.48-2.15], P < 0.0001), especially for cardiovascular (HR: 2.47 [95% CI: 1.81-3.39], P < 0.001) but also noncardiovascular (HR: 1.48 [95% CI: 1.16-1.87], P ¼ 0.002) deaths. Mortality rates were lower for patients with takotsubo syndrome than those with myocardial infarction (31%, 195/620; HR: 0.76 [95% CI: 0.62-0.94], P ¼ 0.012), which was attributable to lower rates of cardiovascular (HR: 0.61 [95% CI: 0.44-0.84], P ¼ 0.002) but not noncardiovascular (HR: 0.92 [95% CI: 0.69-1.23], P ¼ 0.59) deaths. Despite comparable medications use, cardiovascular therapies were consistently associated with better survival in patients with myocardial infarction but not in those with takotsubo syndrome. Diuretic (P ¼ 0.01), anti-inflammatory (P ¼ 0.002), and psychotropic (P < 0.001) therapies were all associated with worse outcomes in patients with takotsubo syndrome. CONCLUSIONS In patients with takotsubo syndrome, cardiovascular mortality is the leading cause of death, and this is not associated with cardiovascular therapy use. (