Flat and depressed neoplastic lesions of the colorectum [Paris type (PT) 0-II] localized to the superficial submucosal (sm) layer can be managed using endoscopic mucosal resection. Successful endoluminal management can be enhanced using endoscopic or ultrasound tools that help predict the degree of sm invasion. Previous studies addressing invasive depth estimation using high-magnification chromoscopic colonoscopy showed a low specificity for deep sm layer 3 invasion with miniprobe ultrasound demonstrating better nodal and T stage in vivo prediction. High-resolution vascular mapping of lesions can show microvascular superficial changes that may predict sm invasive disease. Vascular mapping in combination with high-magnification chromoscopic colonoscopy (HMCC) may provide an accurate tool for the invasive depth estimation of PT type II neoplastic lesions as compared with high frequency 20/12.5 MHz miniprobe ultrasound. Sixty-eight patients with a known diagnosis of PT II neoplasia were imaged using 3 "back to back" imaging modalities. Phase 1-vascular ectasia mapping; phase 2-HMCC with crypt analysis according to Nagata criteria; phase 3-12.5/20 MHz miniprobe ultrasound. Lesions predicted as T0/1/N0 were resected using endoscopic mucosal resection with the remaining referred for surgery. Each imaging modality was then compared with the resected histopathologic specimen used as the "gold standard." N=68 lesions (19 sm1/13 sm2/36 sm3). Overall accuracy of Nagata criteria, Nagata criteria combined with vascular mapping, and ultrasound staging was 65%, 78%, and 94%, respectively (P<0.001) when observing the between phase differences. Fifty-two lesions were resected surgically. The prevalence of node positive disease was 16% (8/52) with the remaining 44/52 (84%) being confirmed pN0 at histopathology. The kappa coefficient of agreement between invasive depth estimation (using histopathology as the gold standard), Nagata stage, Nagata stage plus vascular ectasia mapping and ultrasound stage was 0.47, 0.65, and 0.9, respectively. A significant improvement in between phase differences was observed (P=0.001). This is the first study to address the in vivo clinical utility of vascular mapping in combination with HMCC for the T and N staging of PT II neoplasia. Combination imaging may provide an adequate clinical tool for both T and N stage assessment in vivo and help stratify those patients at high risk for T2/N1 disease that may benefit from further high-frequency miniprobe ultrasound (HFUS) assessment and possible primary surgical excision. This is important in the clinical context, given the high overall costs of a second HFUS examination, limitation of HFUS resources, and safe selection of patients undergoing primary endoscopic resection versus surgical resection.