Purpose <p>To determine whether preoperative D-dimer and intraluminal thrombus ratio interact to predict aneurysm expansion in patients with persistent type 2 endoleak after endovascular aneurysm repair, informing candidate selection for prophylactic embolization.</p> Materials and methods <p>This retrospective single-center study analyzed 138 patients with persistent type 2 endoleak confirmed at 12-month follow-up after elective infrarenal endovascular aneurysm repair (2007–2020). The primary outcome was aneurysm expansion ≥ 10&#xa0;mm within 5&#xa0;years, assessed by Cox models with a D-dimer × intraluminal thrombus ratio interaction term and generalized estimating equations for continuous diameter change. Patients were stratified by median D-dimer (4.1&#xa0;μg/mL) and median intraluminal thrombus ratio (41.5%).</p> Results <p>During median follow-up of 4.7&#xa0;years, 27 patients (19.6%) developed the primary outcome. High D-dimer predicted expansion overall (hazard ratio 3.37; 95% confidence interval 1.39–8.21; <i>P</i> = 0.007). Within the high intraluminal thrombus ratio stratum, high D-dimer conferred markedly elevated risk (hazard ratio 13.06; 95% confidence interval 1.69–101.24; <i>P</i> = 0.014; Firth's regression: hazard ratio 8.29; <i>P</i> = 0.015); D-dimer was not predictive in the low intraluminal thrombus ratio stratum (P = 0.46). The three-way generalized estimating equations interaction was significant (<i>P</i> = 0.015); annual diameter change diverged markedly (+ 2.18 vs. + 0.04&#xa0;mm/year), with a 12.6-mm difference at 60&#xa0;months (<i>P</i> = 0.003).</p> Conclusion <p>Preoperative D-dimer and intraluminal thrombus ratio interact to predict midterm aneurysm expansion. In patients with high thrombus burden, D-dimer identifies a high-risk subgroup and a low-risk subgroup amenable to standard surveillance.</p> Level of Evidence <p>Level 3b, Retrospective cohort study.</p> Graphical Abstract <p></p>