Cyclophosphamide is the most commonly used agent as antineoplastic chemotherapy. The aim of this study was to detect its chronic effect on urinary bladder & liver which included biochemical, histopathological and immunohistochemical changes in adult rats and to evaluate the possible protective effects of nigella sativa oil (NSO). Fifty adult albino rates were assigned equally to 5 groups (control, physiological  saline  (0.15ml I.P daily),  NSO (2ml/kg orally daily),  Cyclophosphamide (15mg/kg I.P daily) and Cyclophosphamide + NSO (the same previous doses). All drugs were given for 8 weeks. By the end of 8th week,  rats given cyclphosphamide alone  had  significantly  higher  MDA (malonodialdahyde), blood glucose level, liver functions and plasma lipid profile but it had lower reduced glutathione and hemoglobin concentration levels than the untreated control rats. Pre- treatment of cyclophosphamide with NSO had ameliorative  effect  on the studied parameters. Light microscopic examination revealed apoptotic like picture in urinary bladder and liver's rats induced by cyclophosphamide. Immunohistochemical study showed obvious high immunolabelling for activated Caspase-3 in the same organs. Mild apoptotic changes were observed in rats received combined cyclophosphamide and NSO (group V). Consequently, NSO significantly ameliorates chronic cyclophospamide toxicity.