Introduction: The Transthyretin Amyloid Cardiomyopathy [ATTR-CM] is a progressive disease, that is characterized by the accumulation of misfolded proteins in the myocardial tissue, leading to progressive heart failure. Tafamidis is the only approved treatment for ATTR-CM and in patients, receiving Tafamidis, a lower rate of decline in the 6 min walk test distance has been reported (ATTR-ACT). Nevertheless, extensional evidence above short follow up periods for improvement in physical performance [PP] is still lacking. Purpose: The purpose of this prospective analysis was to assess the PP in patients with ATTR-CM at baseline compared to follow-up visits over a long-term follow-up period. Methods: Patients underwent Cardiopulmonary exercise testing [CPET] and blood testing at baseline, first follow-up [1st FUP] (9 ± 3 months after initiating Tafamidis therapy) and second FUP [2nd FUP] (19 ± 12 months after initiating Tafamidis therapy). We analysed CPET parameters during rest, exercise and recovery and laboratory values prior to CPET. The baseline data was compared with data from 1st FUP and 2nd FUP. Concerning cohorts, patients at baseline were Tafamidis naïve, while patients at 1st FUP and 2nd FUP received Tafamidis 61mg once daily during entire study duration of 26 (± 11) months. An improvement in VO2 at maximum level of exercise [VO2 max] was defined as an increase in ∆max VO2 ≥ 1 mL/kg/min, compared to baseline. A decline was defined as a negative ∆max VO2 mL/kg/min compared to baseline. Results: We analysed 11 male patients, with a median age at study entry of 75 (± 9) years and a median Body Mass Index of 26 kg/m2 (± 6 kg/m2). Use of Betablockers was higher at 2nd FUP compared to baseline (54.5% vs 27.3%). Further, Diuretics and/or mineralocorticoid antagonist use was higher at 2nd FUP compared to baseline (63.6% vs. 54.5%). We analysed 33 CPET measurements, evenly divided into baseline, 1st FUP and 2nd FUP. Maximal physical performance was increased at 1st FUP compared to baseline (104.27 Watt vs. 91.45 Watt), but reduced at 2nd FUP compared to 1st FUP (99.36 Watt vs. 104.27 Watt). An increase in VO2 max was evaluated in the 1st FUP compared to baseline (18.75 mL/kg/min vs. 17.70 mL/kg/min). Further, we observed a reduction of VO2 max at 2nd FUP compared to the baseline values (15.80 mL/kg/min vs. 17.10 mL/kg/min). Minute ventilation and exhaled CO2 [VE/VCO2] slope was higher in 1st FUP compared to baseline (35.96 vs. 35.38) and higher compared to 1st FUP (30.31 vs. 35.96). Long term assessment of laboratory values, such as high sensitivity Troponin-T showed an increase at 2nd FUP compared to baseline by 19.30% (51.00 ng/L vs. 42.75 ng/L), further assessment showed a worsening in N-terminal pro brain natriuretic peptide value by 12.14% by comparing 2nd FUP versus baseline (2194.56 ng/L vs. 1956.93 ng/L). Conclusion: ATTR-CM is a progressive disease, a decline of physical performance under Tafamidis and optimal background therapy is common in ATTR-CM patients. Future studies are needed to evaluate the benefit of specific interventions such as rehabilitation to maintain and improve physical performance in ATTR-CM patients.