Objectives and background: The aim of the study was to evaluate the long-term effects of tafamidis on cardiac disease progression beyond 12 months of treatment by performing (among others) serial multi-parametric cardiovascular magnetic resonance (CMR) studies in patients with transthyretin (ATTR) cardiac amyloidosis (CA) cardiomyopathy (ATTR-CM). Methods: Patients with confirmed ATTR-CM ( N = 56) were divided into two groups: in the larger group A ( N = 39; 95% male), treatment with tafamidis 61 mg once daily was initiated after the first CMR study, whereas group B ( N = 17; 76% male) comprised ATTR-CM patients who did not receive tafamidis. The observational follow-up period lasted 27 ± 6 months. During this period, patients underwent two multi-parametric CMR studies at our institution as part of a routine clinical observation pipeline. Results: Clinical symptoms assessed by the NYHA class showed a slight, however, significant increase in both groups. NT-proBNP levels substantially increased in both groups at follow-up, however, with a significantly higher increase in the tafamidis-naïve group B ( p = 0.014). LV systolic function, defined by LV-EF and 3D global longitudinal peak strain, significantly worsened in both groups at follow-up (54% to 48% p < 0.001 vs 56% to 46%, p < 0.001; −7.4 to −5.3, p < 0.001 vs −8.8 to −4.8, p < 0.001). However, the tafamidis-naïve group B experienced a substantially higher impairment of both parameters when compared to group A (∆p = 0.008 and ∆p = 0.003, respectively). LV wall thickness considerably increased in both groups at follow-up, however, with a significantly higher increase in the tafamidis-naïve group B (from 18.2 mm to 21.1 mm at follow-up, p < 0.001) compared to the tafamidis-treated group A (from 18.5 mm to 19.2 mm, p = 0.012; ∆ p < 0.001). Both global native T1 and global ECV values were significantly elevated in both groups—at baseline and at follow-up—with a significant increase in both groups during follow-up. However, a substantially higher increase in global ECV was observed in the tafamidis-naïve group B compared to the tafamidis-treated group A (group A: 51% to 57%, p < 0.001; group B: 50% to 67%, p < 0.001; ∆p < 0.001). Conclusion: Substantial worsening of clinical symptoms, serum biomarkers, and imaging parameters occurred in both tafamidis-treated and tafamidis-naïve ATTR-CM patients within a follow-up period of approximately 2 years. However, the “extent of worsening” is significantly lower in the tafamidis-treated compared to the tafamidis-naïve patients. Graphical