Background: Nesfatin-1 is a novel peptide possessing pleiotropic metabolic effects. No-reflow phenomenon (NR) is a poor prognostic indicator occurring in around 30% of all patients undergoing primary percutaneous coronary interventions (pPCI). Inflammation and complexity of coronary artery disease (CAD) play pivotal roles in the pathogenesis of NR. In this study, we investigated the relationship between admission serum nesfatin-1 level, NR and complexity of CAD assessed by SYNTAX-1 (SS-1) and SYNTAX-2 (SS-2) scores in patients with ST-segment elevation myocardial infarction (STEMI) undergoing pPCI. Methods: A total of 174 STEMI patients who underwent pPCI were included in the study and divided into NR (n = 36) and normal flow (n = 138) groups. Serum nesfatin-1 was measured by enzyme-linked immunosorbent assay. Seventy-eight consecutive age-, gender- and co-morbidity-matched patients undergoing coronary angiography with < 50% stenosis comprised the control group. Results: Nesfatin-1 levels were significantly lower in the NR group compared to the normal flow and control groups (10.8 6.6 ng/mL vs. 34.9 24 ng/mL vs. 43.6 23.2 ng/mL, respectively, p < 0.001). Nesfatin-1 was significantly and inversely correlated with SS-1 and SS-2 scores (r = -0.709 and r = -0.655, respectively, both p < 0.001). Multivariate logistic regression analysis showed that nesfatin-1 [odds ratio (OR) = 0.81, 95% confidence interval (CI) = 0.708-0.936, p = 0.004] and glomerular filtration rate (OR = 0.94, 95% CI = 0.892-0.989, p = 0.018)were independently associated with NR. In the receiver operating characteristic analysis, nesfatin-1 < 15.21 ng/mL predicted NR with 78.4% sensitivity and 72.2% specificity (area under the curve = 0.809, 95% CI = 0.701-0.918, p < 0.001). Conclusions: Admission nesfatin-1 level is a potent predictor of NR in STEMI patients undergoing pPCI. Additionally, nesfatin-1 has a robust and negative correlation with the complexity of CAD.