Since the bulk of human epididymis protein 4 (HE4) studies was conducted in oncology facilities, it is uncertain how useful serum HE4 is in guiding referral decisions in patients with an ovarian tumor. While ovarian cancer is uncommon at general hospitals, these facilities make the referral decision. Researchers evaluated the accuracy of 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 at 9 different community hospitals were prospectively enrolled. Preoperative measurements of HE4 and CA125 determined the risk of malignancy index (RMI). The histological analysis was used as the gold standard. There were a total of 316 individuals, 195 of whom had a benign ovarian tumor, 39 had borderline growth, and 82 had a malignant one. 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. Though it may be better, HE4 is now being used to help decide which patients with ovarian masses should be sent to an oncology facility for further evaluation.