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Takotsubo cardiomyopathy (TC) develops in patients who are under significant emotional, psychosocial, or sudden biochemical stress. However, the added burden of TC on the patients receiving chemotherapy has never been studied. We aimed to describe the additional clinical and economic burden, along with the potential predictors of TC and related in-hospital mortality in patients receiving chemotherapy using the largest inpatient cohort. We identified chemotherapy-related adult hospitalizations using the National Inpatient Sample databases (2010 to 2014). Primary end points were the incidence of TC and the odds of in-hospital mortality. Secondary end points were gender-based incidence differences, length of stay (LOS), hospital charges, and discharge disposition. We identified 1,067,977 chemotherapy-related hospitalizations, of which, 562 hospitalizations revealed TC incidence. Other co-morbidities were also significantly higher in the TC cohort. In unmatched analyses, the LOS (median 17 days vs 5 days) and total hospital charges (median $162,825 vs $46,335) were significantly higher in the TC group. A propensity-matched analysis confirmed the increased healthcare burden. Multivariate analysis revealed over 2-times higher odds (odds ratio [OR] 2.17) of in-hospital mortality in the TC group. Female gender (OR 2.48), and nonelective (OR 2.26), and nonfederal government hospital (OR 2.68) admissions had more than twice the odds of developing TC. An advanced age, Asian race, urban-teaching hospital, and complications such as septicemia, fluid-electrolyte disorders, cardiogenic shock, and respiratory failure independently raised mortality odds in the TC group. In conclusion, we observed an overall increasing nationwide trend in TC incidence in patients receiving chemotherapy, which adds to significantly increased in-hospital mortality, LOS, and healthcare charges.