Abstract Background The coexistence of aortic stenosis (AS) and cardiac amyloidosis (CA) is common. If treated with transcatheter aortic valve implantation (TAVI), patients with the combined phenotype (AS-CA) have a comparable short term survival to those with lone AS, whereas data on longer term outcomes is currently lacking. Purpose This study aimed to evaluate the clinical outcomes of AS-CA compared to lone AS over a 5-year follow-up. Methods Using a prospective, multicentre, observational, case-control design, we screened consecutive patients with severe AS referred for TAVI for co-existing CA. CA screening included blinded 99mTc-DPD bone scintigraphy (Perugini Grade-0 negative, 1-3 increasingly positive) with additional SPECT/CT and light chain assessment prior to intervention. Transthyretin CA (ATTR) was diagnosed by bone scintigraphy and unremarkable light chain assessment, light-chain CA (AL) by endomyocardial biopsy. Mortality (all-cause and cardiovascular [CV]) and hospitalisation for heart failure (HHF) were captured as clinical endpoints. Results 376 patients (83±7 years, 52% female, EuroSCORE-II 4.9±2.9) were recruited, of which 43 (11.4%) had AS-CA (42 ATTR, 1 AL). Compared to lone AS, patients with AS-CA were older with higher cardiac biomarkers (NT-proBNP, high-sensitive Troponin-T) and a higher prevalence of atrial fibrillation. Heart team decision yielded valve replacement in 320 (85%) and conservative management in 56 (15%) patients, without differences between AS-CA and lone AS. Over a median follow-up of 5.4 (Q1: 4.9; Q3: 5.7) years, 230 (61.1%) patients died and 67 (17.8%) experienced HHF (with a total HHF number of 91). AS-CA was associated with higher all-cause mortality (crude HR 1.64, 95%CI 1.15-2.35; log-rank, p=0.006), which remained significant after multivariate adjustment for clinical confounders (EuroSCORE-II, valve replacement; adjusted HR 1.63, 95%CI 1.15-2.32; p=0.006). AS-CA was not associated with CV mortality (log-rank, p=0.18) or time to first HHF (log-rank, p=0.43), but the rate of HHF was significantly higher in AS-CA compared to lone AS (5.7 versus 3.5 per 1,000 patient years, p=0.022). Conclusions Among elderly patients referred for TAVI, long-term outcomes of AS-CA are characterized by higher mortality and a higher rate of heart failure hospitalisations compared to patients with lone AS. Studies evaluating the role of CA-specific treatments are warranted in this population.