BACKGROUND: Recent studies have suggested a high prevalence of cardiac amyloidosis (CAm) in heart failure (HF) patients. CAm might be underdiagnosed owing to low clinical suspicion. METHODS AND RESULTS: We performed retrospective analysis of 259 patients with HF and ejection fraction (EF) ≥50% referred for endomyocardial biopsy. Seventy-three (28%) had CAm. Multivariable independent predictors of CAm were identified. Over a mean follow-up of 2.6 ± 3.3 years, CAm patients had worse survival than those without (1.5 y vs 6.3 y; log rank P < .0001). CONCLUSIONS: Clinicians should be suspicious of CAm in patients with EF 50%-75%, >50 years of age, BMI <30 kg/m2, peripheral neuropathy, Sokolow-Lyon index ≤15 mm, and septal wall thickness ≥1.4 cm.