Abstract Aims Layer-specific left ventricular (LV) strain alterations have been suggested as a specific finding in Fabry Disease (FD). Our study aimed to assess the diagnostic value of layer specific radial strain (RS) indices compared to the established LV regional strain pattern in Cardiac Amyloidosis (CA) and FD, i.e. apical sparing, and posterolateral strain deficiency. Methods and Results We retrospectively analyzed the global, subendocardial, subepicardial LV radial strain, the corresponding strain gradient, as well as the regional and global longitudinal strain. The diagnostic accuracy of the diverse LV strain analyses was comparatively assessed using receiver operating curve (ROC) and multivariable regression analyses. In 40 FD and 76 CA patients, CA featured more reduced layer strain values [Global RS -12.3 (-15.6 to -9.6) in CA vs. -16.7 (-20.0 to-13.6) in FD; p < 0.001; subendocardial RS -22.3 (-27.4 to -15.9) vs. -28.3 (-31.8 to -23.6), p < 0.001; subepicardial RS -6.6 (-8.6 to -4.7) in CA vs. -8.9 (-11.7 to- 6.5 in FD; p < 0.001]. Global radial and longitudinal strain held an AUC of 0.75 (0.66 to 0.84) and AUC 0.73 (0.63 to 0.83). While the apical sparing and PLSD strain pattern showed the highest accuracy as single parameters [AUC 0.87 (0.79 to 0.95) and 0.81 (0.72 to 0.89), p < 0.001], the combination of subendocardial RS and the apical sparing pattern featured the highest diagnostic accuracy [AUC 0.92 (0.87 to 0.97)]. Conclusion Combining radial strain derived parameters to the established strain pattern apical sparing and PLSD improve the diagnostic accuracy in the echocardiographic assessment in suspected storage disease.