Background: Prolonged mechanical ventilation (PMV) is a common complication after liver transplantation surgery. However, owing to the clinical and economic benefits of early extubation, many efforts have been used to assess the clinical predictors for PMV. The aim of our study was to explore the impact of perioperative risk factors, including candidate gene polymorphisms, for PMV in patients undergoing liver transplantation. Methods: One hundred forty patients who underwent liver transplantation surgery were enrolled. The duration of mechanical ventilation after surgery was examined, along with the length of intensive care unit and hospital stay, and 30-day mortality. Patient-related clinical factors and single nucleotide polymorphisms of candidate genes were assessed with regard to PMV, which was defined as mechanical ventilation for > 48 h. Results: Twenty-six (19%) patients continued to receive mechanical ventilation at 48 h after surgery. Intraoperative continuous renal replacement therapy (CRRT) and an elevated serum lactate level during the postoperative period were significantly associated with the PMV group, compared to the non-PMV group (odds ratio [OR] = 24.731 [1.077, 567.915] versus OR = 3.008 [1.497, 6.045]). A significant association existed between the HLA-DPA1 rs8486 polymorphism and the risk of PMV under the allele model (OR = 8.060 [1.451, 44.765]). Conclusions The rs8486 polymorphism in HLA-DPA1 can independently affect the risk of PMV in liver transplantation recipients, along with intraoperative CRRT application, and elevated lactate level during the postoperative period.