Background: Anastomotic leakage still remains the most important surgical complication after colorectal surgery. The reported rate of anastomotic leak ranges from 3 to 20% and morbidity can be substantial, with an increased associated mortality of 6–22%. Nowadays no intraoperative tests (as the hydropneumatic assessment) predictive of anastomotic continence are validated. Some factors influencing anastomotic leakage are reported in literature like colonic tension, vascularization and the execution of the proper anastomotic technique. Fluorescence angiography has been shown to be an accurate tool for assessing microperfusion and has been associated with improved outcomes in hepatobiliary, foregut, transplant, and plastic surgery. Aim: The aim of this prospective study was to describe the vascular pattern in colorectal surgery to assess the proximal colonic point of transection (PoT) by near-infrared (NIR) fluorescence perfusion. Materials and Methods: We enrolled 5 consecutive patients undergoing surgery with curative intent for colonic (4 patients) and rectal cancer. All patients underwent a standard oncological laparoscopic resection. After inferior mesenteric artery and vein ligation, wide left colonic mobilization, transection of the rectum, before specimen extraction anesthesiologist administered a bolus of 3.5 mg ICG intravenously. Perfusion of the colon was visualized and evaluated via fluorescence angiography and the line of demarcation between perfused and nonperfused tissue was compared with the initial planned PoT and assessed as inadequate, adequate, or optimal. We used the Quest SpectrumTM Platform imaging system for fluorescence angiography. Results: In four patients, the fluorescence angiography confirmed as optimal the planned PoT otherwise in a patient with ultralow rectal cancer, it was considered inadequate and the correct PoT was re-assessed by the fluorescence angiography. On 30 POD, patients underwent endoscopy and/or barium enema and no anastomotic leakage was reported. Conclusions: We reported our preliminary data of this ongoing prospective study about the use and value of the NIR fluorescence angiography guided surgery to identify the optimal Point of Transection in order to prevent anastomotic leakage.