The aim of this paper is to analyze why ozone can be medically useful when it dissolves in blood or in other biological fluids. In reviewing a number of clinical studies performed in Peripheral Arterial Diseases (PAD) during the last decades, it has been possible to confirm the long-held view that the inverted U-shaped curve, typical of the hormesis concept, is suitable to represent the therapeutic activity exerted by the so-called ozonated autohemotherapy. The quantitative and qualitative aspects of human blood ozonation have been also critically reviewed in regard to the biological, therapeutic and safety of ozone. It is hoped that this gas, although toxic for the pulmonary system during prolonged inhalation, will be soon recognized as a useful agent in oxidative-stress related diseases, joining other medical gases recently thought to be of therapeutic importance. Finally, the elucidation of the mechanisms of action of ozone as well as the obtained results in PAD may encourage clinical scientists to evaluate ozone therapy in vascular diseases in comparison to the current therapies.