Epithelial ovarian carcinoma (EOC) patients often acquire resistance against common chemotherapeutic drugs like paclitaxel and cisplatin. The mechanism responsible for the same is ambiguous. We have identified a putative drug-resistant tumour cell phenotype (EpCAM+CD45+) in the ascitic fluid of EOC patients, which appears to originate from the primary tumour. These cells represent the major tumour burden and are more drug resistant compared to EpCAM+ tumour cells due to the over-expression of SIRT1, ABCA1 and BCL2 genes. We have found that the entire EpCAM+CD45+ population is highly invasive with signature mesenchymal gene expression and also consists of subpopulations of ovarian cancer stem cells (CD133+ and CD117+CD44+). Additionally, we demonstrate that the EpCAM+CD45+ tumour cells over-express major histocompatibility complex class I antigen, which enable them to evade the natural killer cell-mediated immune surveillance. Preliminary evidence obtained in OVCAR-5 cells suggests that exosomes, secreted by non-tumour cells of the ascitic fluid, play an important role in rendering drug resistance and invasive properties to the cancer cells. Identification of such aggressive tumour cells and deciphering their origin is important for designing better drug targets for EOC.