Background <p>Numerous studies have demonstrated that leukocyte-derived composite indices (LDCIs) are closely associated with coronary artery disease (CAD). However, their relationship with premature coronary artery disease (PCAD) remains unclear. This research endeavors to elucidate the relationship between LDCIs and PCAD and to evaluate the predictive accuracy of different LDCIs for PCAD.</p> Method <p>In this cross-sectional study, 211 young and middle-aged adults, who underwent their first coronary angiography (CAG) at the Second Hospital of Jilin University between March 2023 and July 2023 were consecutively enrolled, among whom patients diagnosed with PCAD included both chronic coronary syndrome (CCS) and acute coronary syndrome (ACS). Demographic characteristics, laboratory test results, and CAG results were collected from the patients’ medical records. The neutrophil-to-lymphocyte ratio (NLR) was calculated by dividing the neutrophil count by the lymphocyte count. the systemic inflammation response index (SIRI) was computed as the neutrophil count multiplied by the monocyte count divided by the lymphocyte count; and the lymphocyte-to-monocyte ratio (LMR) was derived by dividing the lymphocyte count by the monocyte count. CAD was defined as having at least one major coronary artery with ≥ 50% stenosis on CAG. Multivariate logistic regression and restricted cubic spline (RCS) analysis were employed to investigate the associations between the NLR, LMR, SIRI, and PCAD. The predictive value of each index for PCAD was assessed using receiver operating characteristic (ROC) analysis.</p> Results <p>Based on the CAG results, individuals diagnosed with CAD were categorized into the PCAD group (<i>n</i> = 143), while those without CAD were categorized into the Control group (<i>n</i> = 68). When LDCIs were analyzed as continuous variables, both SIRI and NLR were identified as independent risk factors for PCAD (OR 1.980; 95% CI 1.168–3.892 and OR 1.416; 95% CI 1.066–2.038, respectively). When LDCIs were analyzed as categorical variables, the highest quartile of SIRI had a 3.481-fold increased risk of PCAD compared to the lowest quartile (OR 3.481; 95% CI 1.140-11.475), while the highest quartiles of the other LDCIs did not show a significant difference in risk compared to their lowest quartiles. In addition, SIRI was the best LDCI for predicting PCAD, with an area under the curve (AUC) of 0.710 (95% CI 0.635–0.784) and positive and negative predictive values of 0.835 and 0.490, respectively. Subgroup analyses showed that the association between SIRI and PCAD remained stable across different subgroups (P for interaction &gt; 0.05); however, the association was more pronounced in females and in non-smokers than in males and smokers.</p> Conclusion <p>Our study found that certain LDCIs are significantly associated with PCAD, with SIRI demonstrating the best predictive performance. This finding may be useful in patients being considered for CAG to help stratify the need for the invasive procedure.</p>