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Introduction Medical therapy in TakoTsubo Syndrome (TTS) remains mainly empirical, given the lack of randomized studies evaluating different pharmacological strategies. The prognostic benefit of angiotensin-converting-enzyme inhibitors and angiotensin II receptor blocker (ACEI/ARB) is not well established. The clinical data published so far are often based on small sample registries and offer opposite results, both in terms of survival and TTS recurrence. Expert recommendations seem favorable to the prescription of ACEI and ARB. Nevertheless, clinical investigation is encouraged for validating the observed results. Purpose The aim of our study was to evaluate the long-term prognostic impact of renin-angiotesin blockers (ACEI or ARB) in terms of mortality and TTS recurrence. Methods The data analyzed in this study were obtained from the nationwide registry “RETAKO”. It included TTS post-discharge survivors, between January 1, 2003, and July 31, 2018. A total of 1062 patients were included for analysis. Cox regression analysis and inverse probability weighting (IPW) propensity score analysis were performed to asses the prognostic benefit of ACEI/ARB. Primary endpoint was a composite outcome of all-cause mortality and TTS recurrence. Results A total of 1062 TTS patients were included. ACEI or ARB were used in 639 patients (60.2%). During a mean follow-up of 2.7±3.5 years, there were 101 deaths (3.9 per 100 patients/year) and 34 recurrences of TTS (1.3 per 100 patients/year). We found no significant difference in follow-up mortality or TTS recurrence in unadjusted and adjusted Cox regression analysis (Hazard Ratio [HR] 0.69, 95% Confidence Interval [CI] 0.47–1.02) between patients treated and untreated with ACEI/ARB. After performing propensity score matching, differences in long term prognosis (all-cause mortality or recurrence) remained no statistically significant (HR 0.73, 95% CI 0.45–1.18). Conclusions In this observational study, we found that ACEI and ARB therapy was not significantly associated with improved long term survival free of recurrence in post-discharged TTS patients. Funding Acknowledgement Type of funding sources: None. Incidence of primary endpoint