Histologic inflammation of placenta has been associated with increased risk for bronchopulmonary dysplasia and periventricular leukomalacia among preterm infants. Tumor necrosis factor-alpha (TNF-alpha) plays a central role in the regulation of inflammation. Some alleles of TNF (LT-alpha+250, TNF-alpha-308, and TNF-alpha-238) have been associated with susceptibility and/or severity of many diseases characterized by inflammation and/or involving the immune system. To determine whether alleles of TNF-alpha affect the risk and/or the severity of chorioamnionitis, we examined the placentas of 101 preterm births (birth weight <or=1250 g) for the presence of inflammation. Maternal and fetal chorioamnionitis (MCA and FCA, respectively) were graded for severity and staged for location of inflammatory infiltrate. Analysis for TNF-alpha alleles was done using PCR-restriction fragment length polymorphism technique on DNA extracted from infants' whole blood. MCA and FCA were seen in 45 and 38 placentas, respectively (p = 0.64). Genotypes of TNF-alpha-308 did not affect the development or the severity of placental inflammation. However, the AA genotype of LT-alpha+250 occurred more often when MCA and FCA were present compared with placentas without inflammation (p = 0.016 and p = 0.007, respectively). The GA genotype of TNF-alpha-238 was more common in placentas with severe MCA than with mild MCA (p = 0.015). The number of A alleles of LT-alpha+250 (GG = 0, GA = 1, AA = 2) correlated directly and significantly with grades and stages of MCA and FCA (p < 0.05). The AA genotype of LT-alpha+250 is associated with the development of chorioamnionitis among preterm births. The A allele of LT-alpha+250 seems to worsen the degree of placental inflammation.