Background <p>Transthyretin amyloid cardiomyopathy (ATTR-CA) is a progressive, fatal disease that often presents as heart failure with preserved ejection fraction (HFpEF). To date, scarce evidence about the economic burden of ATTR-CA has been published. This study compared the economic impact of HFpEF in patients with and without ATTR-CA in Spain.</p> Methods <p>The PRACTICA study was a cross-sectional, multicenter, nationwide study in twenty sites in Spain. A total of 387 consecutive ambulatory or hospitalized patients aged ≥ 50 years with HFpEF and LVH ≥ 12&#xa0;mm were included and screened for ATTR-CA. Healthcare resource utilization (HRU), except specific pharmacologic treatments, non-HRU and its associated average cost per-patient per-year were assessed in year 2021 for ATTR-CA and non-ATTR-CA patients.</p> Results <p>Patients were classified as: ATTR-CA (<i>n</i> = 65), non-ATTR-CA (<i>n</i> = 306) and inconclusive (<i>n</i> = 16). Mean total cost per-patient per-year was higher in ATTR-CA patients: €3,407 (Min-Max: €1,067-€6,473) in ATTR-CA, €3,203 (€1,168-€5,646) in non-ATTR-CA and €2,920 (€1,165-€5,080) in inconclusive patients (<i>p</i> &lt; 0.001, Kruskal-Wallis). Determinants of differential cost favoring ATTR-CA were hospitalizations, genetic testing, implantable cardiac defibrillator, and scintigraphy. No statistical differences were observed between patients with and without ATTR-CA in non-healthcare resources paid by patients themselves, although inconclusive patients showed significantly higher home adaptation (shower, bed rail) and crutch utilization (<i>p</i> = 0.031, Kruskal-Wallis).</p> Conclusions <p>This is the first multicenter nationwide study assessing the economic impact on Spanish society of ATTR-CA patients with HFpEF and LVH ≥ 12&#xa0;mm. The cost was substantial, with negative implications particularly for the Spanish National Health System.</p>