Objective To evaluate left ventricular myocardial work (LVMW) in predicting response to cardiac resynchronization therapy (CRT) using innovative two-dimensional speckle tracking imaging (2D-STI) technology. Methods From December 2017 to October 2019,75 patients with heart failure received CRT in Northern Jiangsu People′s Hospital were selected. Conventional echocardiography was performed before and 6 months after CRT, and global LVMW index (LVMWI) was analyzed with 2D-STI. Patients were defined as responders if a reduction over 15% was observed in left ventricular end-systolic volume(LVESV) after CRT. SPSS statistics 25.0 was used for statistical analysis, and the correlation between variables was analyzed using Spearman correlation. The receiver operating characteristic (ROC) curve was employed to analyze the predictive value of different parameters for the therapeutic effects of CRT. Results The effective rate of CRT was 65%(49/75). Compared with before operation, the responders had lower left ventricular end-diastolic dimension (LVEDD), left ventricular end-diastolic volume (LVEDV) and LVESV, higher left ventricular ejection fraction (LVEF), higher myocardial work index (GWI), higher global effective work (GCW), higher global work efficiency (GWE), and lower overall invalid work (GWW) after the intervention (P<0.05). There were no statistically significant differences in those parameters in the non-responders. Preoperative GCW and GWW were higher in the responders than the non-responders (P<0.05). GCW was linearly correlated with △LVESV and LVEF (r=0.58,0.64; P<0.05 for both). The area under the ROC curve was 0.78 for GCW and 0.85 for GWW in predicting CRT responders (P<0.05). Conclusion The left ventricular myocardial work index can evaluate the left ventricular systolic function in the CRT patients and can be used to predict the response to CRT.