Introduction Biliary fistula (BF) is the most common post hepatectomy complication. Different definitions have been proposed. The International Study Group of Liver Surgery (ISGLS) definition is the most used. The definition adopted in Humanitas Research Hospital (HRH) defines BF as bilirubin concentration in the drain fluid greater than 10 mg/dL on or after POD 3. Various topical haemostatic agents have been developed, their usefulness in preventing BF remains unclear and needs to be assessed. Methods First endpoint: assess the clinical benefit of using Hemopatch to prevent post-operative BF. Secondary endpoint: evaluate the clinical impact of the two definitions. we designed a randomized controlled study on 220 patients: 110 Hemopatch group (group-A) and 110 standard group (group-B), who underwent hepatic resection from 2018 to 2020. All patients were drained. Drains were removed with drain bilirubin concentration less than 10 mg/dL on POD 7. Results BF (ISGLS definition) occurred in 139 (63.5%) patients, 67 (60.9%) in group-B and 72 (66.1%) in group-A (p = 0.515). One-hundred- twenty fistulas (54.5%) were grade A, 18 (9%) grade B, 1 (0.5%) grade C. Considering HRH definition, BF occurred in 19 (8.7%) patients, 6 (5.5%) in group-B and 13 (11.9%) in group-A (p = 0.144). Sixteen (84.2%) were treated conservatively, 2 (10.5%) performed ERCP, 1 (5.3%) underwent relaparotomy. At multivariate analysis the only factor associated with BF increased risk was transection of the main portal branch (OR = 54.35; p = 0.026). Conclusions Hemopatch does not reduce the incidence of BF, considering both the ISGLS and HRH definition. The different rate of BF in the two classification may lead to reconsider its definition.