Ethnopharmacological relevance: Inula viscosa (L.) Aiton is a traditional medicinal plant widely distributed and used in Mediterranean countries, its leaves are prepared by maceration to treat, rheumatic pain, inflammatory diseases, diabetes, anemia and cancer. Aim of the study: The present study purpose to investigate the anti-inflammatory efficacy of I. viscosa leaves methanol extract (IVME) at three different doses on formaldehyde-induced arthritis in NMRI albinos mice. Materials and methods: Mice were divided into six groups (n = 6) as follows: normal control, disease control, Diclofenac group (10 mg/kg, p.o. daily) and three groups, daily treated with 50, 100 and 200 mg/kg IVME (p.o.); Formaldehyde models were obtained by a sub-plantar administration of 20 mu l of formaldehyde (3.75% v/v) into the right hind paws of NMRI albino mice on 1st and 3rd days of the 10 experimental days. Joint diameter was measured, arthritis severity was evaluated by inhibition of paw edema, histological changes, synovial hyperplasia and immune cells infiltration was evaluated by histological and immunohistochemical analyses of CD3(+), CD20(+) and CD68(+). Post-mitochondrial supernatants (PMS) from liver tissues homogenates were collected for the assessment of enzymatic and non-enzymatic antioxidants: Catalase (CAT) & Myeloperoxidase (MPO) activities, glutathione (GSH) and an oxidative stress biomarker (nitric-oxide (NO)) level. Results: Administration of I. visocsa (at low dose: 50 mg/kg) significantly (& lowast;& lowast;& lowast;p < 0.001) ameliorated the induced arthritis severity, reduced hyperplasia of synovial membrane, bone erosion and immune cells infiltration (& lowast;p < 0.05), resulted by restoration of paw diameter. It also decreased levels of NO (& lowast;& lowast;& lowast;p < 0.001) and MPO activity (& lowast;& lowast;& lowast;p < 0.001), and significantly restored GSH levels (& lowast;p < 0.05) and CAT activity (& lowast;& lowast;& lowast;p < 0.001) in liver tissues. Conclusion:<bold> </bold>These findings suggest that I. viscosa leaves have an anti-arthritic property. Which is due to the combination of antioxidant activity regulating oxidative stress and anti-inflammatory effect by probably cytokines regulation.