Hydroxytyrosol (3,4-dihydroxyphenil-ethanol, HT), the major phenol derived from olive oil consumption, has shown different anti-inflammatory and anti-oxidant activities in vitro which may explain the chronic-degenerative diseases preventive properties of olive oil. The aim of this study was to examine the ability of HT reduce inflammatory markers, Cyclooxygenase-2 (COX2) and Tumour Necrosis Factor alfa (TNF-? and oxidative stress in vivo on a mouse model of systemic inflammation. Balb/c mice were pre-treated with HT (40 and 80 mg/Kg b.w.) and then stimulated by intraperitoneal injection of lipopolysaccharide (LPS). Blood was collected to measure COX2 gene expression by qPCR and TNF-? level by ELISA kit in plasma. In addition, the total anti-oxidant power of plasma and the DNA damage were measured by FRAP test and COMET assay, respectively. LPS increased the COX2 expression, the TNF-? production and the DNA damage. HT administration prevented all LPS-induced effects and improved the anti-oxidant power of plasma. HT demonstrated in vivo anti-inflammatory and anti-oxidant abilities. The results may explain the health effects of olive oil in Mediterranean diet. HT represents an interesting molecule for the development of new nutraceuticals and functional food useful in chronic diseases prevention.