Cardiovascular diseases such as chronic limb ische- mia, cardiomyopathies and stroke represent the first cause of death. Moreover, type-II diabetes,  chronic obstructive pulmonary disease and age-related macu- lar degeneration are also progressive pathologies complicated by a chronic inflammation that might be able to maintain progressive chronic oxidative stress. Orthodox medicine has provided excellent drugs which slow down the progression of these diseases but minimally reverse the oxidative stress conditions. Ad- ministration of antioxidants is unable to balance the oxidant excess. Today, all the biochemical and mo- lecular mechanisms of ozone therapy have been clari- fied and it has been demonstrated that ozone therapy can reactivate the fundamental Nrf2 system and be able to restore the innate antioxidant defense mecha- nisms composed of several highly protective enzymes. This paper proposes to integrate the orthodox treat- ment with ozone therapy for improving clinical results.