Background: Fibrin-based biological adhesives are used for tissue adhesion improving the outcome of gastrointestinal sutures. The objective was to assess the effectiveness of fibrin-based biological adhesives for prevention of anastomotic leakage in high-risk gastrointestinal anastomoses. Methods: A randomized clinical trial was designed to recruit patients underwent a rectal resection surgery. A subgroup of patients with rectal anastomosis were recruited from 2 different hospital centres. Patients in which a biological fibrin-based biological adhesive was applied to the suture line (study group) were compared versus a control group under standard practice. The main outcome measures was presence or absence of leakage and need for reoperation. Results: Thirty seven patients underwent a rectal resection and anastomosis. In 21 standard practice was applied and a fibrin-based adhesive was used in 16. Fourteen patients (37.8%) had a clinical or subclinical anastomotic leak, 11 belonging to control group versus 3 patients in the study group (p-value of 0.04). Statistically significant difference (p-value of 0.048) in the need for reoperation. We found no association between the use of drains and anastomotic leakage. There were only 3 leaks in the group in which a drain was placed, as compared to 11 leaks in the group in which no drain was placed, but these findings were probably due to chance (p = 0.54). Conclusions: The use of these adhesives could not only reduce serious postoperative complications related to dehiscence but also improve the prognosis and oncological outcome of rectal and sigmoid cancer treatment.