Abstract. Belay R, Makonnen E. 2018. Anti-inflammatory activities of ethanol leaves extract and solvent fractions of Zehneria scabra (Cucurbitaceae) in rodents. Biofarmasi J Nat Prod Biochem 18: 42-56. Zehneria scarba (L.f.) Sond is one of the medicinal plants used in folkloric medicine of Ethiopia for years to treat various inflammatory disorders. The present study was aimed to validate the anti-inflammatory activity of crude 70% ethanol leaves extract (70EE) against a sub-acute model and further evaluate the solvent fractions (AF, BF, and CF) in an acute (carrageenan-induced paw edema), sub-acute (formaldehyde induced arthritis) and chronic (cotton pellet induced granuloma) inflammatory models. The 70EE was first prepared by maceration, and the fractions were obtained by sequential partitioning with chloroform and n-butanol from the aqueous suspension of crude 70EE. The test groups, then, received 100, 200 and 400 mg/kg of the crude 70EE or the fractions (AF, BF, and CF) at the same dose levels, whereas positive controls received aspirin (200mg/kg) or dexamethasone (0.5mg/kg) and negative controls received vehicle (2% tween 80 or distilled water, 10 mL/kg). All tested doses of the crude 70EE showed significant inhibition of formaldehyde induced arthritis at the 10th day of treatment, on which the 400mg/kg dose showed the maximum anti-arthritic effect (%A = 60.5; p < 0.001). In the carrageenan-induced paw edema, all the three fractions showed a statistically significant effect, in fact, with different onset and magnitude. In this model, the AF was found to be the most active fraction, and the 400mg/kg dose demonstrated the maximum effect (%A = 76.25; p < 0.001) at 5h post-induction, which is much better than the effect of aspirin at the dose employed. The overall order of efficacy in inhibiting the exudative component of carrageenan-induced paw edema was found to be AF> BF> CF. The AF was also found to be the most active fraction in inhibiting the exudative component of chronic inflammation in the cotton pellet induced granuloma model, where the maximum effect (%A = 43.10, p < 0.001) was exhibited by a dose of 400mg/kg. The AF was also the most active fraction in inhibiting formaldehyde induced arthritis, in which the BF and CF relatively showed a comparable effect throughout day 4-10. On the contrary, in the cotton pellet induced granuloma model, the CF was found to be the most active fraction in inhibiting the proliferative and granulomatous component of chronic inflammation, and the overall order of effectiveness was found to be CF> AF> BF. Besides, 400mg/kg of CF demonstrated the maximum inhibition of granuloma formation (%A = 55.52; P < 0.001). The phytochemical analysis revealed the differential distribution of secondary metabolites into the three fractions, which either singly or in concert appeared to be responsible for the observed effects. The data obtained from the present study collectively indicate that the extract and fractions of leaves of Z.scabra possessed a significant anti-inflammatory activity, upholding the folkloric use of the plant.