Glutathione-S-transferases (GSTs) play an important role in the detoxification of chemicals that may lead to mutagenic or cytotoxic effects. In this study, we aimed to find the effect of aqueous, methanol and ethanol extracts of both Ephedra aphylla and Ephedra foeminea on the activity of the purified sheep liver GST at the following different concentrations (0.1, 0.2, 0.4, 0.6, 0.8 and 1 mg/ml) spectrophotometrically using 1-chloro- 2, 4- dinitrobenzene (CDNB) as substrate. The obtained results revealed that all examined extracts types of Ephedra species under study manifested inhibitory effect on GSTs activity at all screened concentrations. The inhibitory effect on GST activity by the alcoholic extracts of the two species under investigation at all tested concentrations was more than the extracts when compared to controls. Nevertheless, this was more pronounced in E. aphylla rather than in E. foeminea. It is worth mentioning that all the GSTs inhibitory effects displayed dose dependent manner under all studied extracts. On that account, the obtained results in this research confirms the medicinal importance of both Ephedra species under study, which provides the possibility of their use in whatever benefit human health in general and combat GSTinduced resistance in drug resistant tumors in particular.