Background: Early recognition and treatment of May-Thurner Syndrome (MTS) is critical in order to avoid the potential complications and irreversible sequelae that may result in lifestyle limitations. The diagnosis of MTS depends on both clinical and imaging findings. The study aimed to compare the efficacy of transabdominal Color Doppler US (CDUS) with that of direct multi-detector computed tomography venography (MDCTV) in the diagnosis of MTS using conventional venography and intravascular ultrasound (IVUS) as gold standard. Patients and Methods: One-hundred patients with clinically suspected MTS were graded by Clinical Etiological Anatomical Pathological (CEAP) classification. All patients underwent transabdominal CDUS of the deep pelvic and lower limbs veins followed by direct MDCTV. Based on venography and IVUS results, the diagnostic performances of both imaging modalities in diagnosing MTS and detecting associated iliofemoral DVT, synechiae, and venous collaterals were quantified. Finally, the degree of agreement between each imaging method and the gold standard and between both modalities was calculated. Results: Conventional venography and IVUS confirmed the MTS diagnosis in 77 out of 100 patients. There was a predominance of females (62%), young and middle-aged (83%), and overweighed patients (60%). MDCTV showed significantly higher accuracy (100%) in diagnosing MTS than that of CDUS (91%) (p=0.008). There was no significant difference between MDCTV and CDUS regarding the detection of iliofemoral thrombus, synechiae, and venous collaterals (all p>0.05). MDCTV and CDUS showed substantial agreement in the detection of venous stenosis, iliofemoral thrombus, and synechiae (k=0.78, 0.77, and 0.72) and almost perfect agreement regarding venous collaterals (k=0.91). Conclusions: Direct MDCTV is a valuable reference in the diagnosis and preoperative workup of MTS with comparable accuracy to that of the more invasive venography and IVUS. Due to its low accuracy in iliac veins evaluation, trans-abdominal CDUS should not be used as the sole investigative tool to confirm or ruled out MTS and combined MDCTV is mandatory.