Background and Objectives: Red cell distribution width-standard deviation (RDW-SD) has been associated with systemic inflammation and adverse cardiovascular outcomes, but its relationship with the angiographic severity and morphological complexity of drug-eluting stent-in-stent restenosis (ISR) has not been systematically characterized. The present study investigated whether RDW-SD is associated with angiographic restenosis severity and restenotic lesion complexity, and compared its performance with the platelet distribution width (PDW), Metabolic Stress Index (MSI), and Platelet-to-HDL Ratio (PHR). Materials and Methods: In this retrospective single-center observational study, 290 patients undergoing clinically indicated repeat coronary angiography following prior drug-eluting stent (DES) implantation were enrolled. Angiographic luminal narrowing was quantified by QCA and categorized as reference (<50% in-stent luminal narrowing; n = 111), intermediate ISR (50-69%; n = 76), and severe ISR (≥70%; n = 103). The Mehran classification was applied to patients with ISR ≥50% and dichotomized as Mehran class I-II (n = 91) vs. Mehran class III-IV (n = 70). Multivariable logistic regression, hierarchical modeling, and incremental discrimination analyses (IDI and NRI) were performed for both binary outcomes. Results: RDW-SD differed significantly across angiographic severity groups (Kruskal-Wallis H = 51.14, p < 0.001), being highest in the ISR ≥70% group [44.6 fL (IQR 43.8-45.3)] and lowest in the ISR 50-69% group [43.2 fL (42.7-43.7)]. A parallel pattern was observed across Mehran class (H = 50.57, p < 0.001; Mehran class III-IV: 44.9 fL [44.2-45.8]). In multivariable analysis, RDW-SD independently associated with ISR ≥70% (OR = 1.228 per 0.5 fL, 95% CI 1.122-1.344, p < 0.001) and Mehran class III-IV (OR = 1.274, 95% CI 1.155-1.406, p < 0.001). Hierarchical modeling showed that adding RDW-SD improved the AUC from 0.603 to 0.719 for ISR ≥ 70% and from 0.592 to 0.757 for Mehran class III-IV (LRT p < 0.001 for both), with incrementally larger IDI and NRI gains for the Mehran class III-IV outcome. PDW did not retain significance after adjustment; MSI and PHR were not significantly associated with either outcome. Conclusions: RDW-SD was independently associated with both angiographic ISR severity and Mehran morphological complexity in patients with established drug-eluting stent restenosis, with numerically greater model discrimination for the Mehran class III-IV endpoint. These findings suggest that RDW-SD may provide complementary information regarding restenosis burden and complexity in patients with established ISR. Prospective studies are required to validate these observations and determine their clinical relevance.