Background and Objectives: Residual coronary anatomical complexity following culprit-lesion-only percutaneous coronary intervention (PCI) remains a major determinant of clinical outcomes in patients with multivessel coronary artery disease (CAD). Platelet distribution width (PDW), a marker of platelet heterogeneity and activation, has been associated with adverse cardiovascular outcomes; however, its relationship with post-procedural residual disease burden remains unclear. This study aimed to evaluate the association between PDW and residual SYNTAX (Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery) score and to determine its incremental predictive value beyond established clinical variables. Materials and Methods: In this retrospective, single-center study, 140 patients with multivessel CAD undergoing culprit-lesion-only PCI followed by planned staged revascularization were included. Clinical presentation was categorized as chronic coronary syndrome (CCS), non-ST-elevation myocardial infarction (NSTEMI), or ST-elevation myocardial infarction (STEMI). Residual SYNTAX score was calculated after the index procedure, and patients were stratified into low (≤22) and high (≥23) groups. Associations between PDW and residual SYNTAX score were assessed using correlation and regression analyses. Model discrimination and incremental predictive value were evaluated using ROC analysis, hierarchical logistic regression, and reclassification metrics. Nonlinear relationships were explored using restricted cubic spline analysis, and clinical utility was assessed by decision curve analysis. Results: PDW was significantly correlated with residual SYNTAX score (Spearman ρ = 0.503, p < 0.001) and increased progressively across SYNTAX severity strata and clinical presentation groups. In multivariable analysis, PDW remained independently associated with high residual SYNTAX score (OR 1.38, 95% CI 1.07–1.82, p = 0.016). The addition of PDW to a hierarchical clinical model significantly improved model performance (ΔR² = 0.049, p = 0.012). Although the improvement in area under the curve (AUC) was modest, reclassification analyses demonstrated significant net reclassification and discrimination improvements. Spline analysis revealed a nonlinear relationship, with a marked increase in risk beyond PDW levels of approximately 13 fL. Decision curve analysis confirmed the clinical utility of PDW across a range of threshold probabilities. Conclusions: PDW is independently associated with post-procedural coronary anatomical complexity and provides incremental predictive value beyond established clinical variables. However, PDW should be interpreted as a biomarker reflecting platelet heterogeneity within a thromboinflammatory context, without the ability to distinguish between acute and chronic components.

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