Aim Platinum-based chemotherapy is widely used for epithelial ovarian cancer (EOC). As high as 20-25% of EOC patients will not respond to the initial chemotherapy. Accumulated evidences have implied that DNA methylation may serve as a potential bio-marker for chemotherapy-resistant phenotypic screening; however, the pattern underlying primary platinum resistance remains unclear. Methods Reduced representation bisulfite sequencing (RRBS) analysis was performed to identify differences in methylation status between primary platinum-resistant patients Progression free survival (PFS) (PFS < 6 months, n = 8) and extreme sensitive patients (PFS >= 24 months, n = 8). The Qubit 3.0 Fluorometer was used for the quantification of RRBS library. The RRBS library was sequenced on Illumina HiSeq2500 sequencer as 50 bp paired-end reads. Results After screening, 94 valid hyper-/hypo-methylated regions were identified to be located within 94 gene promoter and exon regions (adjusted q <= 0.5), which were primarily associated with cell-cell adhesion, B cell activation and lymphocyte activation according to GO analysis. The 19 differentially methylated regions (DMR) located in the promoter region including TRC-GCA11-1, LOC105370912, ANO7P1, DHX4,MSH2, CDCP2, CCNL1, ARHGAP42P2, PRDM13, LOC101928344, USP29, ZIC5,IL1RAPL1, EVX2, ABR, MGRN1, UBALD1, LINC00261, and ISL2 were identified according to the order of P-values from low to high, of which MSH2, LINC00261, MGRN1, ZIC5, EVX2, CCNL1, and DHX40 were presented to play a variety of roles in cancers process based on the previous studies. Conclusion DNA methylome profiling based on RRBS assay is an effective method for screening aberrantly methylated genes in primary platinum-resistant patients, which may serve as a potential epigenetic bio-marker for the prediction of primary platinum resistance.