OBJECTIVE: Our purpose was to determine whether early second-trimester amniotic fluid interleukin-6 levels predict delivery before 34 weeks' gestation. STUDY DESIGN: We used stored second-trimester amniotic fluid samples obtained from women undergoing genetic amniocentesis from 1988 to 1996. Interleukin-6 levels were measured by enzyme-linked immunosorbent assay in samples from every case known to result in delivery from 20 to 34 weeks' gestation (n = 290), and 290 matched controls delivering at ≤37 weeks. Fetal aneuploidies, anomalies, and all cases delivering within 30 days of the amniocentesis (which were thought to be possibly procedure related) were excluded. RESULTS: Interleukin-6 levels were higher in cases than controls (1.9 ± 5.2 vs 1.0 ± 2.4 ng/ml, p = 0.004). Cases were grouped according to whether the preterm delivery was indicated or spontaneous: The mean interleukin-6 levels were significantly higher than controls in the spontaneous group (1.6 ± 3.2 vs 0.8 ± 1.2 ng/ml, p = 0.01) but not in the indicated group (1.4 ± 4.0 vs 0.8 ± 1.2 ng/ml, p = 0.12). In all samples the interleukin-6 level was negatively correlated with the gestational age at delivery (R = -0.11633, p = 0.007). CONCLUSION: Elevated early second- trimester amniotic fluid interleukin-6 levels are associated with preterm delivery, confirming that in some women this indicator of very early intrauterine inflammation predicts birth before 34 weeks' gestation.