Background: Circulating free DNA (cfDNA) and circulating tumor cells (CTC) are new biomarkers for malignant tumors. Its role on ovarian epithelial cancer (OEC) is not yet well stablished. We analyze its role on advanced OEC compared with CA125 and HE4. Methods: Multicentric prospective observational study from November 2013 until February 2017, with OEC patients group (OECG), benign ovarian tumors group (BENIGNG) and health subjects control group (HEALTHG). CTCs were analysed by the CellSearch method and cfDNA by ALU-sequences-based quantitative PCR using two primers (115 and 247 bp); cfDNA integrity was calculated by ALU247/ALU115 ratio. Samples were obtained before treatment (M0), after primary peritoneal surgery (M1), after one cycle of chemotherapy (M2), before (M3) and after interval surgery (M4). This study was approved on May 2013 by the corresponding Central Research Independent Ethics Committee. Results: We analyized 102 subjects from all 3 groups (81 OECG, 14 BENIGNG y 7 HEALTHG); 68% were high grade serous subtype; most frequent staging was IIIC (58%). Within the follow-up (FU) period (average 14 months: min 0, max. 35) 36% relapses and 23% deaths were reported. CTCs were positive on 23% of OECG. In HEALTHG no positive were seen and only 1/14 in the BENIGNG group. Monitoring of cfDNA at the treatment points shows significant differences between M0 and M4 (p = 0.02). No differences were seen in the other determinations. cfDNA-ALU115 was 1.40178 ng / mcL (95% CI 1.18066-1.62290) in the OECG, 0.66383 (95% CI 0.44832-0.87935) in BENIGNG and 0.59923 in HEALTHG ( 95% CI, 0.14449-1.05397). The difference was significant between OECG and BENIGNG (P = 0.017) and near the significance between OECG and HEALTHG (p = 0.69). cfDNA integrity in OECG and HEALTHG was significantly different (P = .012). The area under the curve of Ca125, HE4, CTC, cfDNA and CFDNA integrity was 0.490, 0.526, 0.621, 0.587 and 0.450 respectively. New generation sequencing of circulating TP53 is ongoing. Conclusions: CTC and cfDNA are new biomarkers that might have an important role in the diagnosis and monitoring of OEC.