Background Takotsubo cardiomyopathy (TC) is an established differential diagnosis of myocardial infarction with non-obstructive coronaries with significant interest but limited data on prognostication. We reviewed the characteristics and in-hospital outcomes and developed a novel risk score for TC.Methods Using the National Inpatient Sample data from 2016 to 2020, we identified adult patients (≥18 years) with acute coronary syndrome (ACS) and TC. We divided the cohort into ACS with and without TC and retrieved baseline data. Multivariable regression analysis was conducted to identify factors associated with TC diagnosis and adverse outcomes, leading to the development of a risk-scoring system.Results Among 7 219 004 adult ACS admissions, 78 214 (1.0%) were diagnosed with TC, with a mean age of 68.2 years, 64 526 (82.5%) being female and 5475 (7.0%, compared with 8.4% for other ACS) in-hospital mortality events. Factors significantly associated with TC were female sex (OR 6.78 (95% CI 6.47 to 7.09), p<0.001) and chronic heart failure (OR 1.60 (95% CI 1.54 to 1.66), p<0.001). A novel risk score was developed, including the following parameters: male sex, age >70 years, non-white race, hypertension, hyperlipidemia, history of coronary artery bypass grafting, history of percutaneous coronary intervention, cardiac arrhythmias, renal failure, cardiogenic shock and vasopressor use. The area under curves for in-hospital mortality was 0.716 in the derivation and 0.725 in the validation cohorts.Conclusions TC remains a high-risk diagnosis in a minority of ACS cases, with mortality rates similar to other ACS causes. Our novel risk score offers a valuable tool for risk stratification in patients with TC, but external validation is needed to confirm its utility.