Diabetes mellitus is a major risk factor for peripheral arterial disease and is often associated with inferior outcomes after infra-inguinal bypass surgery. The Omniflow II biosynthetic graft has shown favorable results in various settings, but evidence comparing outcomes between diabetic and nondiabetic patients is lacking. We performed a multicenter retrospective cohort study of 190 infra-inguinal Omniflow II bypasses (2014-2024) across 7 Dutch hospitals. Primary endpoint was primary patency; secondary endpoints included assisted and secondary patency, major amputation, vascular graft or endograft infection (VGEI), and mortality. Differences between diabetics and nondiabetics were assessed using Kaplan-Meier and Cox regression. Of the 190 patients, 62 (32.6%) had diabetes mellitus. The median follow-up was 30 months (interquartile range [IQR] 13-51). Diabetes was not associated with differences in primary patency (adjusted hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.58-1.49, P = 0.78), primary assisted patency (adjusted HR 1.14, 95% CI 0.72-1.81, P = 0.58), or secondary patency (adjusted HR 1.25, 95% CI 0.77-2.02, P = 0.36). Major amputation (adjusted HR 0.85, 95% CI 0.38-1.96, P = 0.72) and VGEI (adjusted HR 2.20, 95% CI 0.38-12.66, P = 0.29) rates were comparable between groups. Mortality was higher in unadjusted analysis (HR 1.76, P = 0.02), but this association disappeared after adjustment (HR 1.50, 95% CI 0.81-2.78, P = 0.20). Despite an unfavorable baseline risk profile, diabetic patients had similar graft-related outcomes compared with nondiabetics. The Omniflow II biosynthetic graft appears to be a safe and effective conduit in this high-risk population.