Depo-medroxy progesterone acetate (DMPA, Depo-Provera) is used in more than 80 countries as a long-acting contraceptive administered as a single intramuscular(i.m) injection of 150 mg/3 months. The present study was set up to investigate the effects of DMPA on 80 average Egyptian women classified into four groups comprising those using the drug for one, two, three and four years, respectively, compared to a control group (N = 20) of married non-hormonally - treated women of similar ages. The drug showed a transient significant elevation of alanine aminotransferase activity (ALT)without an apparent effect on other liver indices, namely total bilirubin (T.Bil) level,aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activities. Only the low density/high density lipoproteins cholesterol ratio (LDLC/HDLC) was gradually and non-significantly (ns) increased in comparison to control group, however, neither total cholesterol (TC) nor triglycerides (TG) were affected by the drug. The lipid peroxide product malondialdehyde (MDA) was significantly elevated in an gradual manner with a corresponding decrease in reduced glutathione (GSH), without any change in blood nitric oxide (NO) levels. It can be concluded that DMPA may be considered as a safe contraceptive medication for the studied group of women, but that special care should be exercised for cardiovascular, hepatic and other patients more sensitive to the harmful effects of free radicals. Alternatively, supportive medications are advisable for each exposed case to secure against the possible irreversible adverse effects of the drug by continuous use. In addition, annual re-evaluation is much more advisable despite the proven safety of the drug.