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Background: May-Thurner Syndrome (MTS) is a potential risk factor for cryptogenic stroke (CS). While retrospective reports have found important association with MTS in CS, prospective data has been lacking. In this study, we prospectively explored the epidemiology and clinical correlates of MTS patients with cryptogenic stroke.Method: Eligible patients were prospectively recruited in accordance with an IRB-approved protocol. All patients underwent full evaluation of etiopathogenesis of stroke such as MRI/MRA, long-term cardiac telemetry (>30 days), echocardiography, and extensive thrombophilia screen (AT3, FV Leiden, Proteins C and S; prothrombin gene mutations, APLAbs, lipoprotein(a), homocysteine) and 1.5T pelvic MRV.Results: We prospectively recruited 1,131 acute ischemic stroke patients, with 59 patients with PFO-related CS; 15 (40.5%) had May-Thurner anatomy (MTA), and 6 (16.2%) had MTS. MTS pts are younger (36.33±9.95 vs. 53.35±14.78, p=0.011), with a lower trend for BMI (24.40±4.87 V.S. 31.13±8.75, p=0.051, table 1). Lower BMI is predictive of MTS in CS (<=22) with high specificity 93.3% (AUC=0.756, p=0.007).Conclusion: In this prospective study, we found MTA and MTS to be very common in PFO CS patients - especially in younger patients with lower BMI and without traditional stroke risk factors. MTS is a novel risk factor that may aide in the diagnosis of PFO CS, and needs further study.