Acute coronary syndrome (ACS) is characterized by unstable plaque with thrombotic process involving central role of platelets. The diagnosis and prediction of significant coronary artery disease (CAD) in non–ST-elevation ACS (NSTE-ACS) can be challenging. The central role of platelets in acute atherothrombosis in NSTE-ACS spurred appreciable interest in the diagnostic and predictive role of platelet activity. Mean platelet volume (MPV) is one of the most promising laboratory markers in patients with CAD. This retrospective study was designed to investigate the diagnostic and predictive value of high MPV levels in patients with NSTE-ACS with significant CAD. A total of 213 patients (men 53%, mean age 61 ± 12.3 years) with NSTE-ACS were enrolled from 2011 to 2016 from 2 teaching hospitals. Patients' demographic, laboratory, and angiographic data were collected. Significant CAD was defined as ≥70% stenosis in at least 1 major coronary artery. Patients with high MPV (MPV ≥9 fl) had more significant CAD (55% vs 35%, p = 0.005), lower platelet count (204 ± 59 × 1,000/μl vs 246 ± 56 × 1,000/μl, p = 0.001), and higher HbA1c (6.9 vs 6.4, p = 0.02). Patients with significant CAD had higher MPV level (9.2 ± 1.07 vs 8.6 ± 1.03 fl, p = 0.001), higher MPV/platelet ratio (0.46 vs 0.40, p = 0.01), older age (64.5 ± 11 vs 59.2 ± 12 years, p = 0.02), and lower high-density lipoprotein level (42 ± 12 vs 47 ± 16, p = 0.01). Multivariate analysis showed that increased age, high MPV, high troponin, and low high-density lipoprotein levels were associated with significant CAD. Patients with high MPV along with high troponin level demonstrated a 4.8-fold increased risk for significant CAD compared to those with normal MPV and high troponin (odds ratio 4.8, 95% confidence interval 1.31 to 17.6, p = 0.001). In conclusion, considering high MPV in the context of elevated troponin level increases the predictive value of screening for significant CAD, and this result may help determine who is most likely to benefit from cardiac catheterization.