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Objectives Premature acute coronary syndrome (PACS) presents with a poor prognosis and significant risks. This study aimed to investigate the association between small-dense low-density lipoprotein cholesterol (sdLDL-C) levels and the severity of coronary lesions, as well as its potential role in risk stratification for PACS patients with multivessel disease (MVD).Design Retrospective cross-sectional study.Setting First Affiliated Hospital of Xinjiang Medical University in China, between May 2022 and November 2023.Participants 900 PACS patients with MVD confirmed by coronary angiography (CAG) and 600 age-matched and sex-matched controls with normal CAG results.Methods Patients with PACS and MVD were stratified by the Global Registry of Acute Coronary Events (GRACE) score, and sdLDL-C levels were compared among the different GRACE score groups. The association between sdLDL-C and the GRACE score was evaluated using Pearson’s correlation analysis. Multivariate logistic regression analysis was employed to identify factors associated with PACS and MVD. The discriminatory ability of sdLDL-C for PACS with MVD was assessed using receiver operating characteristic (ROC) curve analysis. Restriction cubic spline (RCS) analysis was used to examine the potential nonlinear association between sdLDL-C levels and the high-risk groups of PACS with MVD.Results Patients with PACS and MVD exhibited significantly higher sdLDL-C levels compared with control group (p<0.0001). Multivariate logistic regression analysis identified elevated sdLDL-C as an independent factor associated with PACS and MVD (OR =1.327; 95% CI =1.258 to 1.400; p<0.0001). The area under the curve (AUC) for sdLDL-C in discriminating PACS with MVD was 0.846 (95% CI=0.826 to 0.866, with a sensitivity of 94.7% and specificity of 58.0%). Furthermore, sdLDL-C levels were significantly higher in the high-risk group than in the low-moderate risk groups (p<0.0001). A strong positive association was observed between sdLDL-C levels and the GRACE score (r=0.644; p<0.0001). The AUC of sdLDL-C for discriminating high-risk cases of PACS with MVD was 0.841 (95% CI=0.815 to 0.867, with sensitivity of 94.3% and specificity of 62.3%). The RCS curve revealed a significant nonlinear association between increasing sdLDL-C levels and the high-risk groups of PACS with MVD (p value for nonlinearity=0.006).Conclusions Elevated sdLDL-C levels demonstrated a significant association with the risk of PACS and MVD. These findings indicate sdLDL-C may serve as a potential biomarker for risk stratification in this high-risk population. However, causal inferences require validation in prospective studies.Trial registration number ChiCTR2300074166