Epidemiological studies demonstrate that the Mediterranean diet, in which olive oil is the major source of fat, reduces the risk of coronary heart disease and cancer. It has been proposed that the beneficial effects of olive oil not only depend on oleic acid, but are also associated with minor polar compounds (MPC). A positive correlation between inflammation and cardiovascular diseases has long been described, monocyte/macrophages and NF-kappaB playing a pivotal role. The aim of this work was to investigate the effects of an extra-virgin olive oil extract (MPC-OOE), particularly rich in MPC and prepared by some of us, on NF-kappaB translocation in monocytes and monocyte-derived macrophages (MDM) isolated from healthy volunteers. In a concentration-dependent manner, MPC-OOE inhibited p50 and p65 NF-kappaB translocation in both un-stimulated and phorbol-myristate acetate (PMA)-challenged cells, being particularly effective on the p50 subunit. Interestingly, this effect occurred at concentrations found in human plasma after nutritional ingestion of virgin olive oil and was quantitatively similar to the effect exerted by ciglitazone, a PPAR-gamma ligand. However, MPC-OOE did not affect PPAR-gamma expression in monocytes and MDM. These data provide further evidence of the beneficial effects of extra-virgin olive oil by indicating its ability to inhibit NF-kappaB activation in human monocyte/macrophages.