Abstract Objective: To evaluate the influence of microbial invasion of the amniotic cavity (MIAC) and histological chorioamnionitis (HCA) on the intensity of the fetal inflammatory response and the occurrence of fetal inflammatory response syndrome (FIRS) in preterm prelabor rupture of membranes. Methods: One hundred forty-nine women with singleton pregnancies complicated by preterm prelabor rupture of membranes between the gestational ages 24+0 and 36+6 weeks were included in the study. Blood samples were obtained by venipuncture from the umbilical cord after the delivery of the newborn. The umbilical cord blood interleukin-6 (IL-6) levels were evaluated using ELISA kits. The fetal inflammatory response was determined by IL-6 levels, and FIRS was defined as an umbilical cord blood IL-6 > 11 pg/mL. Result: IL-6 levels and the occurrence of FIRS were higher in women complicated with both MIAC and HCA (median IL-6 35.5 pg/mL, FIRS in 68%) than in women with HCA alone (median IL-6 5.8 pg/mL, FIRS in 36%), MIAC alone (median IL-6 2.8 pg/mL, FIRS in 17%) or women without MIAC or HCA (median IL-6 4.3 pg/mL, FIRS in 29%). There were no differences in IL-6 levels or rates of FIRS among women with MIAC alone or HCA alone and women without both MIAC and HCA. Conclusions A higher fetal inflammatory response mediated by umbilical cord blood IL-6 was identified when both MIAC and HCA were detected in pregnancies complicated by preterm prelabor rupture of membranes.