While fate of ovarian failure after chemotherapy has been well established, the precise mechanism by which this occurs is less clear.Recent study has revealed that PTEN/PI3K/Akt signaling in oocytes is critically important for maintenance of the primordial follicle pool. Current study was designed to investigate role of this pathway in cisplatin induced primordial follicle depletion. This was an experimental study using animal model. Mouse was given daily intraperitoneal injection of 2mg/kg (Dong A Pharmaceutical, Korea) for 15days. Ovaries were collected at time point 0, 5, 10, 12, 15 days after the start of daily Cisplatin injection. Ovaries were fixed in PFA and paraffin embedded. Serially sectioned (10μm section) ovarian tissues were H&E stained for differential follicle count. Early stage follicle were counted according to previous definitions after staining with early stage ovarian follicle marker Lhx8. Ovary samples were used for immunohistochemistry and evaluated for apoptosis using Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Antibodies used in western blotting were PTEN, Akt, phospho-Akt, ERK, phospho-ERK, GSK3-β, phospho-GSK3-β and FOXO3a with visualization by enzymatic chemiluminescence. Quantification of the different follicle populations in each time point after Cisplatin injection showed that as cumulative dose of Cisplatin increase, there was significant increase in ratio of growing follicle versus dormant follicles. As with the TUNEL staining, apoptosis was only observed in granulosa cells of growing or mature follicle until day 10 and relatively few primordial follicle was stained compared to growing and mature follicle at day15. Analysis of the PI3K/PTEN/Akt/Foxo3 pathway demonstrated decreased PTEN as cumulative dose of cispaltin increases and activated pathway cascade resulting increase in cytoplasmic translocation of Foxo3 in cisplatin treated follicles. Cisplatin over activates the dormant primordial follicle in mice resulting loss of resting pool of ovarian follicles. Effect of the treatment showed activation of PTEN/Akt/PI3K/FOXO3 pathway thus increase in growing follicle pool while dormant follicles exhibit rapid depletion. Our finding suggests promising therapeutic target for fertility preservation during chemotherapy.