Objective To evaluate the hypothesis that cytokine levels are associated with miscarriage risk using serum samples collected prior to report of miscarriage. Design A nested case-control study. Setting Biospecimens from the multi-site Collaborative Perinatal Project, University of Florida laboratory assessment of IL-1ra, IL-1β, IL-4, IL-6, IFN-γ, TNF-α, TPO and G-CSF. Patients were obtained from cases of miscarriage (N=439) matched to controls (N=373) by gestational age (GA) at sample collection. Intervention None. Main outcome measures Miscarriage. Results Increased risk of miscarriage was associated with elevated TPO (AOR: 1.16, 95% confidence interval (CI):1.00 – 1.36) and decreased G-CSF (AOR: 0.78, 95% CI 0.64 – 0.95). When analysis was restricted to samples collected more than 35 days prior to miscarriage, the effect of G-CSF was not observed (AOR: 0.96, 95% CI 0.72 – 1.28), whereas increased risk related to higher TPO remained. Conclusions Circulating levels of TPO may be associated with increased risk of miscarriage.