Abstract Aims Availability of mortality-reducing therapies for cardiac amyloidosis (CA) has led to an increase in referral rates to tertiary care centers. Investigations to improve diagnosis rates are urgently needed, as diagnosis of CA requires a multimodal approach and its early diagnosis is crucial due to high mortality in untreated patients. The aim of this study is to evaluate the accuracy of the left atrial reservoir strain (LASr) in differentiating CA patients from patients with hypertrophic cardiomyopathy (HCM). Methods This is a cross-sectional analysis from the Graz HCM Registry, a prospective single-center cohort study enrolling consecutive patients with a HCM phenotype. This analysis included HCM and CA patients with valid standardized transthoracic echocardiographic examinations. Blinded investigators performed post-processing echocardiographic analyses in 100 HCM and 95 CA patients. Results Compared to HCM patients, CA patients were more frequently male [79 (83%) vs. 54 (54%); p<0.001] and older [78 (73-81) vs. 58 (47-70) years; p<0.001]. Moreover, CA patients had a lower BMI [25.0 (22.8-26.9) vs. 26.5 (24.3-29.7) kg/m²; p=0.002] as well as lower systolic [134±20 vs. 142±25 mmHg; p=0.018] and diastolic blood pressure [78±12 vs. 84±12 mmHg; p<0.001]. Additionally, CA patients had higher NT-proBNP [2533.0 (1146.0-5016.0) vs. 543.0 (195.0-1381.0) pg/ml; p<0.001] and lower eGFR [58.4±19.1 vs. 80.1±22.2 ml/min/1.73m²; p<0.001]. LASr was significantly worse in CA patients compared to HCM patients [9.2 (5.6-13.0) vs. 21.7 (14.8-27.6) %; p<0.001]. Multivariable logistic regression analysis revealed LASr as an independent predictor of CA [OR=0.936 (95% CI 0.877-0.998)], adjusting for covariates. ROC analysis showed an AUC of 0.80 (95% CI 0.73-0.86) for LASr to discriminate CA from HCM. LASr ≤14.3% demonstrated a 80% sensitivity and 79% specificity for the identification of CA patients. Sensitivity analyses involving 74 sex- and age-matched patients yielded materially unchanged results. Conclusion Compared to HCM patients, LASr was diminished in CA patients and an independent predictor of CA. Moreover, LASr showed high diagnostic accuracy in differentiating CA and HCM patients. Prospective studies are needed to evaluate the added value of left atrial strain in the diagnostic work-up of CA patients.ROC curve of LASr