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Background Dual antiplatelet therapy (DAPT) is commonly used for flow diversion but may increase hemorrhagic complications. The surface-modified flow diverter (FD) p48 MW HPC may allow treatment with prasugrel-based single antiplatelet therapy (SAPT). Our study compared the safety and effectiveness of prasugrel-based SAPT vs DAPT in patients with unruptured saccular aneurysms arising from distal parent vessels treated with p48 MW HPC.Methods We conducted a multicenter, retrospective cohort study of adults with unruptured saccular aneurysms arising from distal parent vessels treated with the p48 MW HPC FD. The primary effectiveness outcome was complete aneurysm occlusion within 12 months. The primary safety outcome was MRI-detected silent ischemic lesions within 48 hours post-procedure, as well as periprocedural complications. Secondary outcomes included hemorrhagic complications, ischemic events, and all-cause mortality within 180 days after treatment.Results Overall, 101 patients were treated (mean age, 60.7 years; 69.3% women). SAPT and DAPT were used in 49 (48.5%) and 52 (51.5%) patients, respectively. Complete occlusion within 12 months was achieved in 79.6% (SAPT) vs 70.6% (DAPT) (P=0.36). Rates of ischemic and hemorrhagic events did not differ significantly (2.0% vs 7.7%, P=0.191; 0% vs 5.8%, P=0.088, respectively). In multivariable analysis, diabetes mellitus was an independent negative predictor of complete aneurysm occlusion (OR 0.26, 95% CI 0.07 to 0.96; P=0.043). Antiplatelet regimen (SAPT vs DAPT; OR 3.39, 95% CI 0.38 to 30.47; P=0.276), aneurysm neck size (P=0.104), aneurysm location (P=0.510), stent diameter (P=0.570), and proximal and distal parent-vessel diameters (P=0.398 and P=0.314, respectively) were not independently associated with complete occlusion.Conclusion In this multicenter retrospective cohort of distal small-vessel flow diversion with the p48 MW HPC, prasugrel-based SAPT was not associated with a significant increase in thromboembolic/ischemic events compared with DAPT; angiographic occlusion and hemorrhage signals were exploratory, with numerically fewer intracranial hemorrhages under SAPT without statistical significance.