Ethnopharmacological relevance: Euclea divinorum Hierns (Ebenaceae) is used in Ethiopian folklore medicine to treat scabies, inflammation of the skin, eczema, abdominal pain, gonorrhea, and kidney problems. However, the claim has not been scientifically validated; Aim of the study: To assess the renoprotective effects of the crude extract and solvent fractions of E. divinorum leaves against gentamicin-induced nephrotoxicity in rats. Materials and method: Rats of either sex were divided into seven experimental groups, each comprising six animals. Group I served as control and given vehicle (Tween 80, 2%, v/v in water) and Group II were treated with gentamicin intraperitoneally (100 mg/kg/day) for eight days. Group III-V received crude extract at three different doses 100 mg/kg, 150 mg/kg and 200 mg/kg, respectively. Group VI received 100 mg/kg of the methanolic fraction and Group VII 100 mg/kg of the aqueous fraction. The extract was administered orally two days before and eight days concomitantly with gentamicin. Following treatment, blood and renal tissue were used to assess creatinine, blood urea nitrogen (BUN), malondialdehyde (MDA), antioxidant enzymes and tubular necrosis using recommended procedures. In addition, free radical scavenging activity was determined using in vitro methods. Results: Gentamicin significantly increased serum creatinine and BUN, MDA and tubular necrosis in rats. It also decreased activity of catalase and superoxide dismutase as well as levels of gluthatione. Pre- and co-treatment with the crude extract and solvent fractions of Euclea divinorum leaves reversed gentamicin-induced alterations as evidenced by a decrease in tubular necrosis, serum and oxidant markers as well as by an increase in antioxidant molecules. Effect was found to decrease with dose when the crude extract was used and maximum protection was conferred by 100 mg/kg of the methanolic fraction in both in vivo and in vitro studies. Conclusions: Euclea divinorum reversed gentamicin-induced nephrotoxicity, probably via its antioxidant activity. The fact that the methanol fraction conferred maximum protection suggests that semi-polar antioxidant principles might be responsible for the observed effect. (C) 2012 Elsevier Ireland Ltd. All rights reserved.