Background: A noninvasive method of determining the severity of coronary artery disease (CAD) is the use of cardiac biomarkers. This study aimed to investigate the use of serum levels of high-sensitivity cardiac troponin I (hs-cTnI) and N-terminal pro–B-type natriuretic peptide (NT-proBNP) in determining CAD severity.Methods: This cross-sectional study included 125 participants categorized by coronary angiographic results into 3 groups: group I (no or < 50% stenosis), group II (1 or 2 vessels with ≥ 50% stenosis), and group III (left main stem or ≥ 3 vessels with ≥ 50% obstruction). Serum hs-cTnI and NT-proBNP levels were measured by enzyme-linked immunosorbent assay. Data were analyzed using SPSS version 25.0 and described as percentages, means, medians, and interquartile ranges (Q1–Q3). Receiver operating characteristic curves and relative quality were applied for both biomarkers.Results: Median hs-cTnI and NT-proBNP levels were higher in group III than in groups I and II (P = .001). Both were higher in group II than in group I (P = .001). Receiver operating characteristic analysis showed that hs-cTnI and NT-proBNP effectively discriminated vascular obstruction severity with high sensitivity and specificity. Relative quality testing results showed a slight increase in predictive ability when the 2 biomarkers were combined.Conclusions: Serum hs-cTnI and NT-proBNP levels, combined or separately, can be used to assess CAD severity concerning the number of diseased vessels, which may help improve risk stratification and management strategy selection. (Iranian Heart Journal 2026; 27(3): 20-26)