Aims: Differentiation between patients with Takotsubo syndrome and acute coronary syndrome (ACS) remains a challenge. We performed a systematic review to identify and evaluate diagnostic predictive models to distinguish both conditions. Methods and results: We performed an electronic search in PubMed, EMBASE, and Scopus until January 2024. Observational studies that developed and/or validated multivariable diagnostic models to differentiate Takotsubo syndrome from ACS were included. The risk of bias was assessed using the Prediction model Risk Of Bias ASsessment Tool (PROBAST). We conducted a narrative synthesis of the performance measures of the diagnostic models evaluated in each study. In addition, a random-effects meta-analysis of the c-statistic with its 95% confidence interval (CI) of the InterTAK model was performed. Of 1015 articles, a total of 11 studies (n = 4552) were included...