Myocardial work derived from pressure-strain analysis resembles a novel non-invasive method for myocardial function evaluation. Left ventricular hypertrophy (LVH) is commonly detected in Fabry disease (FD), cardiac amyloidosis (CA) and hypertension (HTN). The study aimed to demonstrate the characteristics of myocardial work in patients with LVH suffering from FD, CA, and HTN. Echocardiography were performed in patients with LVH suffering from FD (n = 13), light chain associated cardiac amyloidosis (AL-CA) (n = 29) and HTN (n = 72), 25 healthy controls were also included in the current study. Conventional and myocardial work parameters were assessed and compared among FD, AL-CA, HTN and controls. Patients with FD and AL-CA were included in the group of infiltrative cardiomyopathy. Logistic regression analysis was used to identify independent predictors for discriminating infiltrative cardiomyopathy from hypertension. Compared with controls, HTN patients had preserved global work index (GWI) and global constructive work (GCW) and reduced global longitudinal strain (GLS) and global work efficiency (GWE) (p < 0.05), but patients with FD and AL-CA had reduced GLS, GWI, GCW and GWE and increased global wasted work (GWW) (p < 0.05). GWI and GCW could discriminate infiltrative cardiomyopathy from HTN independently with high accuracy (GWI cut-off value 1626 mmHg%, sensitivity 0.87, specificity 0.82, area under the curve 0.90; GCW cut-off value 2021 mmHg%, sensitivity 0.84, specificity 0.88, area under the curve 0.91). GWI and GCW were reduced in FD and AL-CA patients, but not in patients with HTN. Myocardial work had an addictive value in differentiating infiltrative cardiomyopathy from hypertension.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10554-023-02818-w.