Introduction Fetal inflammatory response syndrome associated with acidosis during labor is a high-risk situation for the fetus. This study evaluated hemodynamic, gasometric, and heart rate variability changes during acute fetal inflammatory response syndrome associated with hypoxia, compared with isolated hypoxia. Material and Methods Acute fetal inflammatory response syndrome was obtained via an intravenously injection of lipopolysaccharide derived from Escherichia coli. Hypoxia was induced by repeated umbilical cord occlusions during three phases: mild, moderate, and severe umbilical cord occlusions. Two groups were created with chronically instrumented near-term fetal sheep: one group with isolated hypoxia, the other with hypoxia and fetal inflammatory response syndrome. Hemodynamic, gas parameters, and fetal heart rate variability were compared between the groups. Results The hypoxia and fetal inflammatory response syndrome group had a higher mortality rate (n = 4/9) compared with the hypoxia group (n = 0/9). Gasometric state was altered earlier in case of lipopolysaccharide injection (pH = 7.22 (7.12–7.24) vs 7.28 (7.23–7.34) p = 0.01; lactate = 10.3 mmol/L (9.4–11.0) vs 6.0 mmol/L (4.1–8.2) p < 0.001 after mild occlusions). After mild occlusions, the hypoxia and fetal inflammatory response syndrome group had higher values on seven heart rate variability parameters compared with the hypoxia group. After moderate occlusions, two parameters remained significantly higher. Conclusions During fetal inflammatory response syndrome, fetal adaptation to hypoxia is impaired. In case of fetal infection, acidosis during labor is likely to become severe more rapidly, requiring closer fetal monitoring during labor.