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Background: Treatment of arterial bifurcation lesions using drug-eluting stents (DES) is now common clinical practice and yet the mechanisms governing drug distribution in these complex morphologies are incompletely understood. It is still not evident how to efficiently determine the efficacy of local drug delivery and quantify zones of excessive drug that are harbingers of vascular toxicity and thrombosis, and areas of depletion that are associated with tissue overgrowth and luminal re-narrowing. Methods and Results: We constructed two-phase computational models of stent-deployed arterial bifurcations simulating blood flow and drug transport to investigate the factors modulating drug distribution when the main-branch (MB) was treated using a DES. Simulations predicted extensive flow-mediated drug delivery in bifurcated vascular beds where the drug distribution patterns are heterogeneous and sensitive to relative stent position and luminal flow. A single DES in the MB coupled with large retrograde luminal flow on the lateral wall of the side-branch (SB) can provide drug deposition on the SB lumen-wall interface, except when the MB stent is downstream of the SB flow divider. In an even more dramatic fashion, the presence of the SB affects drug distribution in the stented MB. Here fluid mechanic effects play an even greater role than in the SB especially when the DES is across and downstream to the flow divider and in a manner dependent upon the Reynolds number. Conclusions: The flow effects on drug deposition and subsequent uptake from endovascular DES are amplified in bifurcation lesions. When only one branch is stented, a complex interplay occurs – drug deposition in the stented MB is altered by the flow divider imposed by the SB and in the SB by the presence of a DES in the MB. The use of DES in arterial bifurcations requires a complex calculus that balances vascular and stent geometry as well as luminal flow., Version of Record