For a study, researchers sought to evaluate the accuracy of human epididymis protein 4 (HE4) in distinguishing benign or borderline from malignant tumors in patients presenting to general hospitals with an ovarian mass. Between 2017 and 2021, patients with an ovarian mass were prospectively enrolled in 9 distinct general hospitals. Preoperative measurements of HE4 and CA125 were used to determine a patient’s risk of malignancy index (RMI). Diagnostic histology was considered the gold standard. Among the 316 patients analyzed, 195 had benign, 39 had borderline, and 82 were diagnosed with a malignant ovarian mass. Most effective was HE4, with an AUC of 0.80 (95% CI 0.74-0.86), then RMI (0.71 (95% CI 0.64-0.78), and finally CA125 (0.69 (95% CI 0.62-0.75)). The biomarkers’ effectiveness varied widely depending on the clinical situation. Using multiple HE4 cut-off values that vary with age outperformed using just 1. The number of appropriate referrals did not change. However, the number of patients incorrectly referred decreased by 32% after HE4 was added to RMI. Patients presenting to community hospitals with an ovarian tumor are better served by using HE4 than RMI for malignancy prediction. Just adding HE4 to the RMI made HE4 better than it was before. Patient referral decisions for patients with an ovarian mass to an oncology facility can be aided by HE4, though it still has space for improvement.