Background: Anastomotic leak following Esophagectomy is associated with significant morbidity and mortality. A major determinant of anastomotic success is good vascular perfusion of the gastric conduit. Indocyanine Green fluorescence angiography (ICG-FA) provides real-time intraoperative evaluation of the vascular perfusion of the gastric conduit but its efficacy in reducing in anastomotic failure has not been proven so far in a prospective randomized trial. The aim of this study was to determine the impact of ICG during minimally invasive esophagectomy (MIE) in reducing the rates of anastomotic failure. Methods: It is a single centre Phase-II RCT with an allocation ratio of 1:1 with accrual beginning from September 2023 with planned sample size of 15 patients in each arm. All consenting patients above 18 years with histologically proven esophageal cancer (treatment naïve/neoadjuvant therapy) fit to undergo a major surgery were included. The patients were randomized into the ICG arm and Non-ICG arm. The anastomotic leak rates (studied at POD 7 with an oral contrast study and POD 30), in both arms was the primary endpoint. The utility of ICG in deciding the site of esophago-gastric anastomosis for the patients in the ICG arm was compared to the patients in the control arm where site of anastomosis was decided based on the surgeon’s subjective assessment of the most appropriate site for the same. The role of ICG-FA in bringing about a change of anastomotic site against the surgeon’s subjective assessment was noted in the test arm as one of the secondary end points. A near-infrared camera system was be used for detecting the ICG fluorescence. Evaluation with fluorescence was performed in real-time. Approximately 20 seconds after IV ICG injection, blood flow was confirmed by ICG-FA as it passed through the right gastroepiploic vessels. If vascular perfusion via ICG-FA was well visualized within 60 s, it was defined as a good perfusion zone, while no vascular perfusion or perfusion times > 60 s would indicate a poor perfusion zone. The anastomotic perfusion result using ICG-FA was evaluated by the surgical team and the anastomosis was performed within the good perfusion zone. Results: A total of 30 patients were accrued for the trial, 15 in each arm. Overall, 3 out of 30 patients had an anastomotic leak (10%), all of which were from the Non-ICG arm (20%). There were no leaks noted in the ICG arm. The rate of anastomotic leak within the non-ICG arm was significantly higher than the ICG arm (p = 0.0726). Within the ICG arm, the use of ICG-FA led to a revision in the site of anastomosis in 6 of the 15 patients (40%). Conclusions: The use of ICG-FA has the potential to reduce anastomotic leaks and improve outcomes in MIE while also allowing for enhanced discretion in choosing the optimal site of anastomosis. Its feasibility concludes phase II of the trial and will begin accrual for Phase III. Clinical trial information: CTRI/2023/09/058118.