Aim: Chemical-induced depletion of ovarian follicle pool can lead to premature ovarian failure in rats. In the rat model of 4-vinylcyclohexene diepoxide (VCD)-induced ovarian follicular loss, we tested the hypothesis that Dehydroepiandrosterone (DHEA) could be reversed by short and long-term treatment of follicular loss. Material and Method: All rats were divided into groups for study and treated with dimethylsulfoxide (DMSO) (control group), VCD alone, DHEA and VCD + DHEA for only 15 days. At the end of 15 days, some of the rats were killed as a group of 15 days. Others continued their treatment with DHEA to form groups of 35 and 55 days, respectively. For each animal, follicle numbers were counted and photographed. Results: VCD treatment produced a sustainable state of ovotoxicity throughout the experiment, diminishing the numbers of both primordial and primary follicles (p<0.05). Only VCD-treated rats showed apoptotic cells at very high rates with TUNEL and caspase-3 immunohistochemical staining (p <0.05). On 15th day, concurrent use of DHEA increases the percentages of both normal primordial and primary follicles. More cystic follicles were observed in both VCD- and DHEA-treated rats, compared to controls (p<0.05). Discussion: In this ovotoxicity model with VCD in rats, administration of DHEA provides protection in the number of primordial follicles in the short and long term.