Background ‘Classical’ echocardiographic signs of Fabry cardiomyopathy (FC), such as left ventricular hypertrophy (LVH), posterolateral strain deficiency (PLSD) and papillary muscle hypertrophy may have a limited diagnostic accuracy in clinical practice. Our aim was to evaluate the diagnostic value of left atrial (LA) strain impairment compared to ‘classical’ echocardiographic findings to discriminate FC. Methods In standard echocardiographic assessments, we retrospectively analyzed the diagnostic value of the “classical” red flags of FC as well as LA strain in 20 FC patients and in 20 subjects with other causes of LVH. Receiver operating characteristic (ROC) curve analysis was performed to assess the respective diagnostic accuracy. Results FC was confirmed in 20 patients by genetic testing. In the LVH group, 12 patients were classified by biopsy to have hypertrophic cardiomyopathy, two had hypertensive heart disease, and six LVH combined with borderline myocarditis. Global and regional left ventricular (LV) strain was not significantly different between groups while LA strain was significantly impaired in FC (Left atrial reservoir strain (LASr) 19.1%±8.4 in FC and 25.6%±8.9 in LVH, p=0.009; left atrial conduction strain (LAScd) -8.4%±4.9 in FC and -15.9%±8.4 in LVH, p<0.01). LAScd, with an area under the curve (AUC) of 0.81 [95% confidence interval (CI) 0.66-0.96] showed the highest diagnostic accuracy to discriminate FC. The PLSD pattern showed an AUC of 0.49, quantification of papillary muscle hypertrophy an AUC of 0.47. Conclusion Adding LA strain analysis to a comprehensive echocardiographic work-up of unclear LVH may be helpful to identify FC as a possible cause.