BACKGROUND: Lymphocyte-based inflammatory indices such as monocyte-to-lymphocyte ratio (MLR) have long been recognized as reliable coronary artery disease (CAD) predictors. More recently, novel indices like the Systemic Inflammatory Index (SII), Systemic Inflammatory Response Index (SIRI), and Systemic Immune-Inflammation Index (SIIRI) have emerged. These newer markers offer a more comprehensive assessment of inflammation by integrating multiple immune cell types, potentially enhancing the prediction of cardiovascular outcomes. OBJECTIVES: We evaluated the predictive value of novel inflammatory markers in estimating the pretest probability of severe CAD in high-risk patients. METHODS: We enrolled consecutive patients undergoing diagnostic coronary angiography in a single tertiary care hospital. Inflammatory markers were calculated based on pre-procedural complete blood count laboratory measurements. Severe CAD was defined as critical (>
70 %) and actionable narrowing of a primary coronary artery. Classification performance was assessed using multivariate logistic regression. RESULTS: The study sample included 363 patients (age 58.9± 11 years, 44.9 % females, 30 % severe CAD). In univariate analysis, MLR, SIRI, and SIIRI were significant predictors of severe CAD, with age- and sex-adjusted OR of 1.98 [1.25-3.14], 1.79 [1.24-2.59], and 1.63 [1.11-2.38], respectively. In multivariate analysis, SIRI remained an independent predictor of severe CAD (OR = 1.98, 95 % CI 1.13-3.46, p = 0.02). CONCLUSION: Our results suggest that novel inflammatory markers derived from routine blood tests are predictive of severe CAD in high-risk patients. Such simple, practical, and cost-effective inflammatory markers may enhance cardiac risk stratification and prediction of severe CAD.