Background: Human exposure to cyclophosphamide (CP) is highly frequent because it is widely used chemotherapeutic and immunosuppressive. CP has potential toxic effects on liver and kidney that make it an issue of concern to public health. Selenium (Se) is an essential dietary element with a high nutritional value, immunomodulatory and antioxidant properties. This study aimed to evaluate the protective role of Se against toxic effects of CP in hepatic and renal tissues of adult male albino rats. Methods: The study was carried on 42 adult male albino rats were divided into 6 groups, 7 rats for each group. Group I (Negative control). group II (Positive control): divided into group IIA (Distilled water), group IIB (Normal saline), group III (Selenium), group IV (CP) and group V (CP + Se). The following markers were measured: serum ALT (Alanine aminotransferase), AST(Aspartate transaminase), LDH (Lactate dehydrogenase), Urea and Creatinine. Hepatic and renal tissue MDA (Malondialdehyde), PCC (Protein carbonyl content), catalase, GSH (Reduced glutathione) and IL-6 (Interleukin six). Histopathological and Immunohistochemical staining studies were demonstrated. Results: In CP administrated rats, serum ALT , AST, LDH , Urea and Creatinine levels increased. Also, CP induced elevation in hepatic and renal tissues MDA, PCC and IL-6 and a decrease in hepatic and renal tissues catalase and GSH. Histopathology and Immunohistochemical staining showed that: CP induced histological damages and strong immunoreaction decreased by co-treatment of Se. Conclusion: Administration of Se improved liver and kidney functions and histology beside improvement in oxidative stress and inflammation caused by CP.