Background: The drug interactions between anti-peptic ulcer drugs as misoprostol and omeprazole in gentamicin induced renal impairment in rats. Materials and methods: Thirty-six animals were randomly allocated into 6 equal groups (n=6). The rats in gp1 were given an orally equivalent volume of the solvent (distilled water) once daily for 16 consecutive days and will serve as a negative control group. Rats received gentamycin with a dose of 80 mg/kg intraperitoneal (i.p.) once daily for eight consecutive days in gps (2, 3), followed with misoprostol with a dose of 100 µg /kg, omeprazole with a dose of 20 mg/kg orally daily for other 8 consecutive days either alone or combined together in gps (4,5,6), respectively. All animals were examined and sacrificed at 16^th dpa, while the second group was sacrificed at 8^th dpa. The blood samples were collected and sera were separated and kept for biochemical examination. Kidneys samples were collected for histopathological examination. Results: The impaired kidney rats (gp 2) showed a highly significant increase in serum urea, creatinine and uric acid when compared to treated groups, while no significant difference in sodium and potassium in all groups. Moreover, the total antioxidant capacity showed a highly significant decrease in gps (2, 3), meanwhile, highly significant increase in treated groups. Severe tubulo-interstitial nephritis was shown in gps (2, 3), while moderated lesions were shown in the treated groups (gps 3, 4, 5). Conclusion: It could be concluded that some beneficial drug interactions between misoprostol and omeprazole in gentamicin induced renal impairment.