Background <p>Posthepatectomy liver failure (PHLF) remains the most lethal complication after liver resection. This study aimed to identify preoperative and intraoperative risk factors for PHLF following open hepatectomy using data derived from prospective clinical trials.</p> Methods <p>A pooled secondary analysis of five prospective studies — four randomized controlled trials and one prospective cohort study — was performed, including 515 patients who underwent elective open liver resection between 2007 and 2017 at two high-volume hepatobiliary centers. PHLF was defined according to the International Study Group of Liver Surgery (ISGLS). Liver fibrosis, cirrhosis, and steatosis were assessed by histopathological evaluation of the surgical specimen. Risk factors were analyzed using univariable and multivariable logistic regression models.</p> Results <p>PHLF occurred in 46 patients (9%), 9 Grade A (19.6%), 13 Grade B (28.3%), and 24 Grade C (52.2%) cases. The 90-day mortality rate in the PHLF group was 52.2%, compared to 2.1% in patients without PHLF. On multivariable logistic regression, liver cirrhosis (OR 4.23, 95% CI 1.82–9.84; <i>P</i> &lt; 0.001), liver fibrosis (OR 2.16, 95% CI 1.01–4.62; <i>P</i> = 0.046), and major hepatectomy (OR 4.78, 95% CI 1.87–12.20; <i>P</i> = 0.001) were independently associated with PHLF. Patients with PHLF had significantly higher rates of severe complications (91.3% vs. 34.8%), bile leakage (45.7% vs. 18.6%), posthepatectomy hemorrhage (19.6% vs. 2.3%), and longer hospital stay (35 vs. 12 days).</p> Conclusion <p>In this secondary analysis of prospective trials, cirrhosis, fibrosis, and major hepatectomy were found as independent risk factors for PHLF. Preventive strategies should emphasize careful patient selection, functional assessment, and parenchyma-sparing surgery.</p> Clinical trial registration <p>Not applicable.</p>