Growing evidence shows that COVID-19 is associated with an increase in Tako-Tsubo syndrome (TTS) incidence. We collected data from patients hospitalized in our multidisciplinary COVID-19 department who had a diagnosis of TTS during the second and third waves of the pandemic in Italy. We reported four cases of TTS associated with COVID-19. Except for COVID-19, no patient had any classical TTS triggers. The mean age was 72 years (67-81) and all patients had COVID-19-related interstitial pneumonia confirmed by computed tomography. Typical apical ballooning and transitory reduction in left ventricle (LV) systolic function with a complete recovery before discharge were observed in all patients. The mean LV ejection fraction at TTS onset was 42% (40-48%). The electrocardiogram showed ST-segment elevation in two cases, while an evolution with negative T waves and corrected QT prolongation was observed in all patients. Three patients underwent coronary angiography. Two patients had Alzheimer's disease. The time interval from hospital admission to TTS onset was 4 (2-6) days, and the time interval from COVID-19 symptom onset to TTS diagnosis was 10 (8-12) days. COVID-19 may be a trigger for TTS, though TTS pathophysiology in COVID-19 patients remains unclear, likely due to its multifactorial nature.