The aim of this study was to investigate the effects of direct creatine infusion on fetal systemic metabolic and cardiovascular responses to mild acute in utero hypoxia. Pregnant ewes (n=28) were surgically instrumented at 118 days gestation (dGa). A constant intravenous infusion of creatine (6 mg.kg-1.h-1) or isovolumetric saline (1.5 ml.h-1) began at 121 dGa. After 10 days, fetuses were subjected to 10-minute umbilical cord occlusion (UCO) to induce mild global hypoxia (saline-UCO, n=8; creatine-UCO, n=7) or sham UCO (saline-control, n=6; creatine-control, n=7). Cardiovascular, arterial blood gases and metabolites, and plasma creatine were monitored prior to, during, and then for 72 hours following the UCO. Total creatine content in discrete fetal brain regions was also measured. Fetal creatine infusion increased plasma concentrations 5-fold but had no significant effects on any measurement pre-UCO. Creatine did not alter fetal physiology during the UCO or in the early recovery stage, up to 24 hours after UCO. During the late recovery stage, 24-72 hours after UCO, there was a significant reduction in the arterial oxygen pressure and saturation in creatine fetuses (PUCO x TREATMENT = 0.02 and0.04, respectively). At 72 hours after UCO, significant creatine loading was detected in cortical grey matter, hippocampus, thalamus and striatum (PTREATMENT = 0.01-0.001). In the striatum, the UCO itself increased total creatine content (PUCO = 0.019). Overall, fetal creatine supplementation may alter oxygen flux following an acute hypoxic insult. Increasing total creatine content in the striatum may also be a fetal adaptation to acute oxygen deprivation.