Introduction: Tachycardia-induced cardiomyopathy (TCM) has been known for decades as a reversible form of non-ischemic cardiomyopathy. However, its mechanism and properties remain poorly understood. Methods: This retrospective study investigated endomyocardial biopsy samples from 18 patients with TCM and compared them with samples from 170 patients with dilated cardiomyopathy (DCM), and 496 patients with inflammatory cardiomyopathy (ICM). Results: 684 patients with recent-onset heart failure and reduced ejection fraction not caused by valvular or ischemic heart disease were analyzed. In the TCM group, 81% were male, mean age was 60±13 years, and 94% had heart failure symptoms ≥2 NYHA class. At baseline (BL), 78% had atrial fibrillation/flutter, and 11% inappropriate sinus tachycardia, heart rate was higher compared to DCM and ICM patients (122±25 versus 78±21; p<0.001). Mean ejection fraction at BL was lower compared to DCM and ICM (27±12% versus 39.0±14.6%; p=0.001), but improved significantly more during follow-up (FU) (20% versus 6%; p<0.001). At FU, heart rate and presence of sinus rhythm were similar in all groups. 69% of TCM patients underwent electrical cardioversion or ablation. Compared with DCM patients, TCM patients had a stronger myocardial expression of MHC class II and an equal amount of infiltration with T-cells/macrophages. Compared with ICM patients, the presence of T-cells/macrophages was significantly lower in TCM. The marker of apoptosis (caspase 3) was comparably elevated in TCM/ICM patients. Conclusion: TCM is characterized by immuno-histological changes comparable to DCM except for caspase 3 levels, which were similar to those in ICM.