The present study analysed the effects of hydroxytyrosol (HT) on blood lipids, antioxidant status and the progression of aortic lesions in hyperlipemic rabbits. Sixty-four rabbits were distributed into eight groups of animals (n = 8). Animal groups C, A and H were fed for 1-month with a control diet containing sunflower oil (C), an atherogenic diet (A) high in saturated fat and cholesterol or the A diet together with HT, respectively. The other five groups were fed for 2-months with diets C or A (groups CC or AA, respectively), or for 1-month with the A-diet followed by a further month with diet C, extra virgin olive oil diet (O) or diet C with HT (groups AC, AO and AH, respectively). Four milligram of HT/kg body weight were used in the study. Fifty and 42% decrease in total cholesterol and triacylglycerols, respectively, and a 2.3-fold increase in HDL-cholesterol were observed in the AH group but not in the H group. The HT-supplemented groups improved their antioxidant status and reduced the size of atherosclerotic lesions measured as intimal layer areas of the aortic arch when compared with control animals. We conclude that HT supplementation may have cardioprotective effects in vivo.