Angiographic high thrombus burden (HTB) is associated with increased adverse cardiovascular events in patients with ST-elevation myocardial infarction (STEMI). HbA1c and C-peptide are two interrelated bioactive markers that affect many cardiovascular pathways. HbA1c exhibits prothrombogenic properties, while C-peptide, in contrast, exhibits antithrombogenic effects. In this study, we aimed to demonstrate the value of combining these two biomarkers in a single fraction in predicting HTB and short-term mortality in patients with STEMI. 1202 patients who underwent primary percutaneous coronary intervention (pPCI) for STEMI were retrospectively included in this study. The study population was divided into thrombus burden (TB) groups and compared in terms of basic clinical demographics, laboratory parameters and HbA1c/C-peptide ratios (HCR). In addition, short-term mortality of the study population was compared according to HCR and TB categories. HCR values were significantly higher in the HTB group than in the LTB group (3.5 ± 1.2 vs. 2.0 ± 1.1; P < 0.001; respectively). In the multivariable regression analysis, HCR was determined as an independent predictor of HTB both as a continuous variable [odds ratio (OR): 2.377; confidence interval (CI): 2.090-2.704; P < 0.001] and as a categorical variable (OR: 5.492; CI: 4.115-7.331; P < 0.001). In the receiver operating characteristic (ROC) analysis, HCR predicted HTB with 73% sensitivity and 72% specificity, and furthermore, HCR's predictive value for HTB was superior to HbA1c and C-peptide. The Kaplan-Meier cumulative survival curve showed that short-term mortality increased at HTB. In addition, HCR strongly predicted short-term mortality in Cox regression analysis. In conclusion, HCR is closely associated with HTB and short-term mortality in STEMI patients.