OBJECTIVES: Khat, an amphetamine like psychoactive plant, is chewed by many people in East African and Middle Eastern countries. Significant number of studies has been conducted to demonstrate its acute and chronic toxic effects to the central nervous system. However, limited or no information is available with regard to peripheral dangers of psychoactive agents including khat. Therefore, this issue deserves investigation.  METHODS: Sixty four healthy Sprague Dawely rats were divided into eight experimental groups of eight animals and khat was administered in different doses (100 mg/kg, 200 mg/kg and 400 mg/kg orally) for ten days. Following administration, animals were killed by light ether anesthesia and blood and renal tissue were used to measure renal markers, including creatinine, blood urea nitrogen, antioxidant enzymes as well as markers for lipid peroxidation and histopathological studies. RESULTS: Administration of khat at high dose (400 mg/kg) significantly caused marked renal dysfunction as evidenced by increased serum creatinine (p<0.001), blood urea nitrogen (p<0.001), and lipid peroxidation (P<0.001), whereas renal superoxide dismutase and catalase enzymatic activities were decreased (p<0.001) compared to control animals. Furthermore, disturbed renal indices by gentamicin were considerably accentuated by high dose (400 mg/kg) of crude khat extract when given concurrently with gentamicin. Khat alone or with gentamicin was also found to alter renal histopathology. CONCLUSIONS: The collective data from this study indicate that khat results a direct nephrotoxic potential, albeit to a small extent, creates synergism when combined with other nephrotoxic agents such as gentamicin.