Introduction: Drug-coated balloons with Paclitaxel aim to address restenosis in lower extremity interventions, but concerns persist about Paclitaxel's distal embolization and drug delivery efficiency. Hypothesis: "Nodular" calcium exhibits poorer drug transfer than "smooth" surfaces during intervention.Aims:To investigate the impact of plaque morphology on drug transfer in advanced scanning electron microscopy (SEM). Methods: Vessels from amputated legs were sectioned into 5 mm samples, longitudinally halved, air-dried, gold-coated, and examined via high-vacuum SEM. Two preselected samples (one “nodular” and one “smooth” surface) were scanned with 300x300 micron field of views (FOVs), covering the surface for both samples. Drug coverage area was classified per FOV into percentage categories (minimal=0-25%, moderate=26-50%, good=51-75%, 4=76-100%) (Fig1A). Results: SEM analysis provided 104 and 107 300x300 micron FOVs for the “nodular” and “smooth” samples, respectively. Distribution of drug coverage categories differed significantly between “nodular” and “smooth” lesions (p<.001) (Fig1B). "Nodular" sample had lower overall drug coverage than "smooth", with a median of “good” coverage in “nodular” vs. “minimal”-“moderate” coverage in “smooth” sample” (p<.001). For the “nodular” surface, 50% of FOVs had “minimal” drug coverage (vs. 11% of “smooth” surface FOVs, p<.001). “Excellent “coverage was observed in 38.31% of “smooth” sample FOVs compared to 10.58% “nodular” FOVs (p<.001). Most of the drug in "nodular" lesion concentrated on the top of the nodule, while "smooth" exhibited uniform distribution. Conclusions: “Nodular” calcification may impede homogenous drug transfer, while a “smooth” surface allows for more effective drug delivery. Our approach contributes to a better understanding of drug delivery in lower extremity PVIs, ultimately guiding personalized treatment and laying the groundwork for innovative device development.