OBJECTIVE: To assess whether the analysis of high sensitivity C-Reactive Protein (hsCRP), a biomarker of inflammation, and placental growth factor (PlGF), a biomarker of placental dysfunction, could help identify patients at risk for preterm birth (PTB). METHODS: We performed a prospective cohort study of women with symptoms of preterm labor (22-33 6/7 weeks). Maternal serum was analyzed for hsCRP and PlGF. Median biomarker values were used as analytic cut-points. We performed chi-square tests of association between biomarkers and PTB, nonparametric tests to compare medians, and logistic regression to determine the odds of PTB associated with biomarker values. Test characteristics of each biomarker were calculated. RESULTS: 56.3% of the cohort (N = 96) delivered preterm. Median hsCRP (N = 78) was 4.34 mg/L, and median PlGF (N = 86) was 558.25 mg/l. In the setting of inflammation (high hsCRP), women with low PlGF had a 6.84-fold (95%CI: 1.57-29.80) increased risk of PTB. In the setting of placental dysfunction (low PlGF), women with high hsCRP had a 5.97-fold (95%CI: 1.52-23.43) increased risk of PTB. CONCLUSIONS: Our results suggest an interplay between inflammation and placental dysfunction in the pathogenesis of PTB. Analyzing biomarkers that reflect different pathways of PTB may hold promise for identifying patients at greatest risk.