Background and Aims: In liver transplantation, cold preservation induces ischemia, resulting in significant reperfusion injury. Hypothermic oxygenated machine perfusion (HMP-O₂) has shown benefits compared to static cold storage (SCS) by limiting ischemia-reperfusion injury. This study reports outcomes using a novel portable HMP-O₂ device in the first US randomized control trial. Approach and Results: The PILOT trial (NCT03484455) was a multicenter, randomized, open-label, noninferiority trial, with participants randomized to HMP-O₂ or SCS. HMP-O₂ livers were preserved using the Lifeport Liver Transporter and Vasosol perfusion solution. The primary outcome was early allograft dysfunction. Noninferiority margin was 7.5%. From April 3, 2019, to July 12, 2022, 179 patients were randomized to HMP-O₂ (n=90) or SCS (n=89). The per-protocol cohort included 63 HMP-O₂ and 73 SCS. Early allograft dysfunction occurred in 11.1% HMP-O₂ (N=7) and 16.4% SCS (N=12). The risk difference between HMP-O₂ and SCS was −5.33% (one-sided 95% upper confidence limit of 5.81%), establishing noninferiority. The risk of graft failure as predicted by Liver Graft Assessment Following Transplant score at seven days (L-GrAFT₇) was lower with HMP-O₂ [median (IQR) 3.4% (2.4–6.5) vs. 4.5% (2.9–9.4), p=0.024]. Primary nonfunction occurred in 2.2% of all SCS (n=3, p=0.10). Biliary strictures occurred in 16.4% SCS (n=12) and 6.3% (n=4) HMP-O₂ (p=0.18). Nonanastomotic biliary strictures occurred only in SCS (n=4). Conclusions: HMP-O₂ demonstrates safety and noninferior efficacy for liver graft preservation in comparison to SCS. Early allograft failure by L-GrAFT₇ was lower in HMP-O₂, suggesting improved early clinical function. Recipients of HMP-O₂ livers also demonstrated a lower incidence of primary nonfunction and biliary strictures, although this difference did not reach significance.