The impact of preformed donor-specific antibodies (DSA) in liver transplantation (LT) remains controversial despite evidence linking their presence to an increased risk of early allograft damage, as well as antibody- and T-cell-mediated rejection. In this nationwide analysis, preformed DSA were assessed using single-antigen bead assays [positive if mean fluorescence intensity (MFI) ≥1000]. This study included all LT recipients enrolled in the Swiss Transplant Cohort Study (STCS) who underwent LT between 2014 and 2016. One-year post-LT outcomes, including cumulative allograft and patient survival, as well as the incidence of biliary, vascular, and infectious complications, were compared between DSA-positive (DSA+) and DSA-negative (DSA-) individuals. Among 321 LT performed in 306 patients, preformed DSA were detected in 92 (28.7%) and more frequently observed in patients with a history of prior transplantation ( p =0.008) or autoimmune liver disease ( p =0.036). Class I and II DSA were present in 48.9% and 71.1% of DSA+ cases, with concomitant class I and II DSA in 20.7%. The median (IQR) cumulative MFI (cMFI) of the preformed DSA was 3768 (1875-10,537), and 52.2% of DSA+ patients harbored multiple DSA. While overall patient survival did not differ between DSA+ and DSA- individuals, DSA+ patients with cMFI ≥5000 exhibited a higher incidence of allograft failure and biopsy-proven rejection. Multivariate analysis revealed that the presence of preformed DSA was independently associated with biliary complications (HR 2.26, 95% CI 1.17-4.37, p =0.02) but not with vascular or infectious complications. In summary, preformed DSA were associated with biliary complications, increased rejection, and reduced allograft survival. These findings suggest pre-transplant immunological risk assessment and the need for tailored immunosuppressive strategies in LT.