Objective: The rarer allele of a polymorphism within the promoter region at position –308 of the gene for tumor necrosis factor ⍺ is associated with increased gene transcription. In this study we tested the hypothesis that this rarer allele is associated with spontaneous preterm birth. Study Design: We conducted a case-control study of women admitted to our labor and delivery unit. To assess data from a single racial group with a high incidence of preterm birth we restricted our analysis to African American women, who contributed 73.6% of the samples collected during the study period. Case patients (n = 55) were defined as women who were delivered before 37 weeks’ gestation after idiopathic preterm labor or preterm premature rupture of membranes. Control subjects (n = 110) included women who were delivered after 37 weeks’ gestation and had no history of preterm delivery. We also performed subgroup analyses of women with idiopathic preterm labor and delivery (n = 29) and women who were delivered preterm after preterm premature rupture of the fetal membranes (n = 26). Results: Although carriers (homozygotes plus heterozygotes) of the rarer allele of the polymorphism at position –308 in the gene for tumor necrosis factor ⍺ were not significantly more common among women who were delivered preterm (n = 24/55, 44%) than among control subjects (n = 33/110, 30%, P = .08, odds ratio 1.81, 95% confidence interval 0.92-3.54), carriers of the rarer allele were more common among women who were delivered preterm after preterm premature rupture of membranes (n = 15/26, 58%) than among control subjects (P = .008, odds ratio 3.18, 95% confidence interval 1.33-7.83). Conclusions: Our results demonstrate an association between allelic variants of the polymorphism at position –308 in the gene for tumor necrosis factor ⍺ and preterm birth after preterm premature rupture of the fetal membranes. We hypothesize that host susceptibility to environmental factors, such as hyperresponsiveness of the gene for tumor necrosis factor ⍺ to genital tract infection, may promote preterm premature rupture of the fetal membranes and subsequent preterm delivery. (Am J Obstet Gynecol 1999;180:1297-302.)