Oleuropein, a phenolic compound present in olives and extra virgin olive oils, is endowed with in vivo beneficial health effects and might be considered a functional food ingredient. Here, we investigated the health effects of neutraceutical oleuropein supplementation (0.59% w/w) on energy balance at the whole body and molecular level in mice fed a high fat diet (HFD). Oleuropein supplementation (HFD¿+¿O) prevented HFD-induced body weight gain resulting in a body weight that was comparable to that of normal fat diet (NFD)-fed mice. Furthermore, indirect calorimetric data, motoric movements, serum glucose and leptin levels, serum and hepatic lipid levels, adipocyte size and adipose tissue gene expression showed an improved health status compared to the control HFD-fed mice. In fact, it appeared indistinguishable between HFD¿+¿O-fed mice and NFD-fed mice. Initially, oleuropein might decrease intestinal energy uptake, while on the longer term weight maintenance could be related to an increased satiety signal. Our results indicate that oleuropein supplementation to a HFD can improve health by reducing adiposity.