Objectives: We aimed to investigate the relationship between myocardial performance index (MPI) and severity of coronary artery disease, as assessed by the Gensini score (GS), in patients with non-ST-segment elevation myocardial infarction (NSTEMI). Methods: Ninety patients with an initial diagnosis of NSTEMI were enrolled in our study. They were divided into tertiles according to the GS: low GS < 19; mid GS > 19 and ≤ 96; and high GS > 96. Results: The low-, mid- and high-GS groups included 24, 38 and 28 patients, respectively. Clinical features such as gender distribution; body mass index (BMI); prevalence of diabetes mellitus, hypertension and hyperlipidaemia; and smoking status were similar in the three groups. MPI and isovolumic relaxation time were significantly higher in the high-GS group than in the low- and mid-GS groups (p < 0.001 and p = 0.005, respectively). Furthermore, the high-GS group had a significantly lower ejection fraction and ejection time (p = 0.01 and p < 0.001, respectively). MPI was positively correlated with the GS (r = 0.47, p < 0.001), and multivariate regression analysis showed that MPI was an independent predictor of the GS (β = 0.358, p < 0.001). Conclusions: Patients with NSTEMI who fall within the high-risk group may be identified by means of a simple MPI measurement.