The relationship between myocardial infarct size (MIS) on late gadolinium-enhanced cardiac MRI (LGE MRI) and myocardial work (MW) indices assessed with MW echocardiography (MWE) has not been well characterized. This study aimed to determine an impaired MW using MIS in patients with acute myocardial infarction. Left ventricular (LV) two-dimensional speckle-tracking echocardiography, MWE, and LGE MRI were performed in 33 patients with ST-segment elevation myocardial infarction and in 30 age- and sex-comparable controls. LV global longitudinal strain (GLS), global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE) and MIS were acquired, respectively. MIS was negatively correlated with GWI (r = -0.60, P = 0.005), GCW (r =- 0.66, P = 0.002) and GWE (r = -0.71, P = 0.0004), but positively correlated with GLS (r = 0.68, P = 0.001). With the receiver operating characteristic curve, the cutoff value of MIS for the prediction of an impaired GLS was 16.5% [area under the curve (AUC) = 0.867)], an impaired GWI was 19.2% (AUC = 0.727), an impaired GCW was 19.2% (AUC = 0.725), an increased GWW was 15.8% (AUC = 0.656), an impaired GWE was 15.8% (AUC = 0.880). MIS is a strong predictor of impaired MW. Timely reduction of infarct size is essential to improve myocardial function.