The main aim of this work is to gain insight into the potential mechanisms of hydroxytyrosol (HT) and its mainplasmatic metabolites (HTmet) that improve the endothelial function. Feeding ApoE−/−mice with 10 mg/kg/day of HT derivatives for 12 weeks significantly reduced E-selectin, VCAM-1, MCP-1, ICAM-1, and F4/80 ex-pression compared with the control group in the isolated aorta. Furtherin-vitromechanistic assays revealed thatboth HT and HTmet could reduce the adhesion of Jurkat-T-lymphocytes to human aortic endothelial cells at1–5 μM, significantly greater reductions being observed with HTmet. This process appeared to be regulated bythe MAPK pathway through the inactivation of p38δ, JNK1-3, CREB, AKT3, p53 and P70 S6 Kinase. We con-cluded that supplementation with HT precursors from olive oil might attenuate the initial steps of atherosclerosisat a molecular level. The reduction of lymphocyte adhesion and the modulation of MAPK pathway by HTmetcould explain this phenomenon.