Objective To investigate the value of serum human epididymal protein 4 （HE4） combined with micrornas （mirnas） -200a/200b/200c in exosomes in the early diagnosis of glycochain antigen 125 （CA125） negative epithelial ovarian carcinoma （EOC）. Methods A total of 120 patients with CA125-negative EOC were selected as the study group， and 115 patients with ovarian epithelial benign tumor admitted during the same period were selected as the benign group. Another group of 107 healthy women who underwent physical examination in wuhan firsthospital were selected as the control group. The levels of HE4， CA125， miRNA-200a， miRNA-200b and miRNA-200c were compared among the three groups. The value of serum indexes in differentiating CA125-negative EOCs and benign ovarian epithelial tumors was analyzed by receiver operating characteristic （ROC） curve. Results The levels of HE4， miRNA-200a， miRNA-200b and miRNA-200c in the study group were significantly higher than those in the benign group and control group， statistically significant differences between the groups （P < 0.05）. ROC analysis confirmed that serum HE4， miRNA-200a， miRNA-200b， and miRNA-200c could be used for the diagnosis of CA125-negative EOC. The combined diagnosis by HE4+miRNA-200a/b/c could obtain a higher area under the curve than the single or pair-based diagnosis （P < 0.05）. Logistic stepwise regression analysis confirmed that， HE4 ≥ 163.110 pmol/L， miRNA-200a ≥ 2.700 2^-△CT， miRNA-200b ≥ 1.665 2^-△CT， miRNA-200c≥ 1.395 2^-△△CT were the risk factors for CA125-negative EOC （P < 0.05）. Conclusion Serum HE4， miRNA-200a， miRNA-200b and miRNA-200c can be used in the early diagnosis of CA125-negative EOC. The diagnosis with the four indicators combined has higher sensitivity and specificity.