<b>Background:</b> Cyclophosphamide (CPA) induces acute inflammation of the urinary bladder, renal damage, and liver damage, thereby limiting its therapeutic use. <b>Objectives:</b> The present study aimed to evaluate the hepatorenal toxicity induced by cyclophosphamide and amelioration by 5-fluorouracil<b> </b>in male albino rats. <b>Materials and Methods:</b> Twenty-eight male adult rats were grouped randomly into four groups (n=5 for each group). Group I (control): Rats were injected with saline intraperitoneally and at a dose of 1.0 ml/kg b.w. for 14 days. Group II cyclophosphamide (CPA): Cyclophosphamide at a dose of 10 mg/kg day by day through i.p. to rats for 14 days. Group III Fluorouracil (5-FU): 5-Fluorouracil at a dose of 10 mg/kg day by day in saline was given through i.p. to rats for 14 days. Group IV (CPA+5-FU): Rats were given CPA followed by 5-FU at a dose of 10 mg/kg per day (day by day) through i.p. to rats for 14 days. At the end of the experimental period, rats were anesthetized using light ether. Blood samples were taken and prepared for biochemical measurements. <b>Results:</b> Serum total protein, albumin, and globulin concentration significantly reduced in animal groups that received cyclophosphamide. 5-FU and CPA combination reduced the changes in total protein, albumin, and globulin compared to CPA treated group. A significant increase in LDH serum concentration was found in CPA, 5-FU, and their combination-treated animals. The mean values of the combination of chemotherapy were above that in CPA followed by 5-FU treatment. Administration of CPA, 5-FU resulted in a significant increase in serum AST, ALT, ALP, and bilirubin compared to the control. Co-treatment 5-FU with CPA significantly attenuated the increase in serum AST, ALT, ALP, and bilirubin when compared to CPA – treated rats. Compared to controls, urea and creatinine levels were increased in CPA-treated rats, while uric acid was reduced in CPA, 5-FU, and their combination. The changes in urea and creatinine produced by the chemotherapy were restored when rats received CPA in combination with 5-FU. <b>Conclusion: </b>It could be concluded that the treatment of mammals with chemotherapy is associated with the production of free radicals that lead to hazardous alterations in biochemical parameters. However, 5-FU and CPA combination could produce a significant amelioration in most cases for these changes, and it may be considered as a potentially useful candidate in the combination chemotherapy with CPA to combat oxidative stress-mediated non-target organ injury even if it was not complete protection. Future work should consider combined chemotherapy regimens, as two or more mechanisms of action of chemotherapeutic drugs could be more powerful than one mechanism. Toxicological studies must be performed before using drugs as a combination before application. Further research is required on the toxicological impacts of drugs and pollutants mixtures.
