Objective: The fetal inflammatory response syndrome is a subclinical condition frequently present in preterm labor and preterm premature rupture of the membranes and is associated with increased perinatal morbidity and mortality. Tumor necrosis factor α is a mediator of septic shock and death, and it exerts its biologic effects by interacting with 2 receptors, TNF-R1 and TNF-R2. Soluble tumor necrosis factor receptors can buffer the biologic activity and protect against the deleterious effects of tumor necrosis factor α. The purpose of this study was to determine the behavior of soluble tumor necrosis factor receptors in fetuses with and without fetal inflammatory response syndrome. Study Design: Fetal blood sampling was performed in patients with preterm labor (n = 95) and preterm premature rupture of the membranes (n = 39). Control samples were obtained from fetuses who were undergoing blood sampling for clinical indications and had normal outcomes (n = 21). Fetal inflammatory response syndrome was defined as a fetal plasma interleukin 6 concentration >11 pg/mL. Concentrations of interleukin 6 and TNF-R1 and TNF-R2 were determined by use of sensitive and specific immunoassays. Analysis of covariance was used for statistical analysis. Results: (1) TNF-R1 and TNF-R2 were detectable in all samples, and their concentrations decreased with advancing gestational age (r = –0.8 and r = –0.7; P <.0001 and P <.001, respectively). (2) The mean fetal plasma concentrations of TNF-R1 and TNF-R2 were significantly higher in fetuses with fetal inflammatory response syndrome than in those without the syndrome after adjustment for gestational age and fetal membrane status (TNF-R1: no fetal inflammatory response syndrome, mean ± SE, 3473.7 ± 128.8 pg/mL; vs fetal inflammatory response syndrome, mean ± SE, 4079.9 ± 190.7 pg/mL; P <.005; TNF-R2: no fetal inflammatory response syndrome, mean ± SE, 6033.2 ± 235.4 pg/mL; vs fetal inflammatory response syndrome, mean ± SE, 7783.1 ± 342.8 pg/mL; P <.0001). (3) Fetuses of patients who delivered within 72 hours of cordocentesis had significantly higher concentrations of TNF-R1 and TNF-R2 receptors than those with longer latency periods (P <.05 for each). Conclusion: The fetal inflammatory response syndrome is associated with increased availability of the soluble receptors of tumor necrosis factor α in fetal plasma. These factors may attenuate the deleterious effects of tumor necrosis factor α. (Am J Obstet Gynecol 2000;183:1070-7.)