OBJECTIVE: The purpose of this study was to determine whether interleukin-1 receptor antagonist and/or interleukin-1beta gene polymorphisms influence multifetal pregnancy outcome. STUDY DESIGN: Maternal and neonatal buccal swabs from 51 multifetal gestations were analyzed for interleukin-1 receptor antagonist and interleukin-1beta alleles. Outcome data were obtained subsequently. RESULTS: Fetal carriage of interleukin-1 receptor antagonist allele 1 was more than twice as prevalent as the carriage of allele 2. Preterm premature rupture of membranes was observed in 12 of 24 pregnancies (50.0%) in which 2 fetuses tested positive for interleukin-1 receptor antagonist allele 2, as opposed to only 3 of 27 pregnancies (11.1%) in which 1 or neither fetus tested positive for interleukin-1 receptor antagonist allele 2 (P=.005). Similarly, 20 of 26 neonates (76.9%) with documented morbidity tested positive for interleukin-1 receptor antagonist allele 2, as compared with 36 of 78 neonates (46.2%) without morbidity (P=.007). Fetal or maternal interleukin-1beta polymorphisms or maternal interleukin-1 receptor antagonist polymorphisms were unrelated to pregnancy outcome. CONCLUSION: Fetal carriage of interleukin-1 receptor antagonist allele 2 was associated with both preterm premature rupture of membranes and neonatal morbidity in women with multifetal pregnancies.