Objective: Cancer Antigen 125 (CA125), the biomarker in common clinical use for ovarian cancer, is limited by low sensitivity for early disease and high false positives. The aim of this study was to evaluate several candidate biomarkers, alone or in combination, compared to CA125. Design: A prospective observational cohort study Setting: St. James’s Hospital (SJH), a tertiary referral centre for gynaecological malignancy in Dublin, Ireland. Population: 274 patients undergoing surgery for symptomatic pelvic masses between 2012 and 2018. Methods: Preoperative Human Epididymis Protein 4 (HE4), the Risk of Ovarian Malignancy Algorithm, the Risk of Malignancy Index I and II, D-dimer, and fibrinogen were assessed. Logistic regression models were fitted for each biomarker alone and in combination. AUCs and pAUCs in the 90-100% specificity range were determined. Main Outcome measures: The accuracy of biomaker(s) in the prediction of malignant/borderline versus benign tumour status compared to CA125. Results: 89 pre- and 185 post-menopausal women were included. In premenopausal women, no biomarker(s) outperformed CA125 (AUC 0.73; 95% CI 0.63-0.84). In postmenopausal women, HE4 had a pAUC of 0.71 (95% CI 0.64-0.79) compared with 0.57 (95% CI 0.51-0.69) for CA125 (p = 0.009). HE4 + D-dimer had an improved pAUC of 0.74 (95% CI 0.68-0.81, p < 0.001). Conclusion: A novel biomarker panel of HE4 + D-dimer outperformed CA125 alone as a high specificity biomarker in postmenopausal women and could aid in the preoperative triaging of symptomatic pelvic masses.