Women who deliver preterm are at increased risk for cardiovascular disease, but mechanisms are not understood. The authors considered that inflammation in women with spontaneous preterm birth (sPTB) might be related to their metabolic profile, such as lipids, and tested this in a nested case-control study from the Pregnancy Exposures and Preeclampsia Prevention Study (1997-2001). Cases were women with sPTB at 34-<37 weeks (n = 76) or < 34 weeks (n = 33). Controls were randomly selected women with term births (n = 228). Early pregnancy inflammation (C-reactive protein: > or = 8 microg/ml) and dyslipidemia (cholesterol: > 230 mg/dl or triglycerides: > 140 mg/dl) were evaluated in serum collected at < 21 weeks. Late pregnancy elevated C-reactive protein (> or = 12 microg/ml) was measured in a subset (n = 295). Polycotomous logistic regression was used to estimate the joint effects of C-reactive protein elevations and dyslipidemia on the risk of sPTB subtypes. After adjustment for race, body mass index, periconceptional vitamin use, and gestational age at sampling, early pregnancy inflammation (odds ratio = 2.9, 95% confidence interval (CI): 1.1, 7.2) and dyslipidemia (odds ratio = 2.0, 95% CI: 1.0, 4.2) were independently associated with sPTB at 34-<37 weeks. The presence of both conditions increased risk of sPTB at < 34 weeks 6.4-fold (95% CI: 1.7, 24.1). Half of the women with early pregnancy inflammation had elevated C-reactive protein late in gestation, and each was independently related to the risk of sPTB at < 34 weeks. The results indicate that some metabolic factors together with inflammation may be related to the risk of sPTB.