Background: We aimed to evaluate the utility of C1 esterase inhibitor, squamous cell carcinoma antigen, and complements C3 and C4 in the prediction of fresh frozen plasma transfusion requirements in postpartum hemorrhage and characterize the involvement of amniotic fluid embolism in the pathophysiology of postpartum hemorrhage. Methods: In this single-centered prospective observational study, consecutive patients with postpartum hemorrhage were evaluated for C1 esterase inhibitor, squamous cell carcinoma antigen, C3 and C4. We analyzed the relationship between the fresh frozen plasma transfusion volume and the above-mentioned biomarkers. The interaction of low C1 esterase inhibitor and squamous cell carcinoma antigen with respect to the fresh frozen plasma transfusion volume was analyzed. Results: The analysis included 132 patients with postpartum hemorrhage. In univariate analysis, C1 esterase inhibitor (correlation coefficient: –0.368, p 0.001), C3 (correlation coefficient: –0.376, p 0.001) and C4 (correlation coefficient: –0.291, p 0.001) were negatively correlated with fresh frozen plasma transfusion volume. In multivariate analysis, only C3 was an independent factor associated with fresh frozen plasma transfusion volume (regression coefficient: –0.173, p = 0.022). C3 had the highest area under the curve (0.843) and cut-off value (80 mg/dL) for the prediction of fresh frozen plasma transfusion of \ge15 units. The fresh frozen plasma transfusion volume was higher in patients with low C1 esterase inhibitor and high squamous cell carcinoma antigen in the interaction analysis. Conclusions: Measuring C1 esterase inhibitor, squamous cell carcinoma antigen, and complements C3 and C4 in postpartum hemorrhage may allow assessment of the extent of anaphylactoid reaction and the requirement for fresh frozen plasma transfusion.