Cigarette smoke contains oxidants such as oxygen-free radicals and volatile aldehydes, which are probably the major causes of damage to biomolecules exposed to cigarette smoke. However, saliva has an antioxidant defense system able to counter toxic activities of radical species that is formed by antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). The purpose of this study is to verify the possible effects of cigarette smoke on SOD and GSH-Px. Forty-four patients (25 males and 19 females) were enrolled in this study. The participants were 20 smokers (12 males and 8 females) and 24 non-smokers (13 males and 11 females). Furthermore, 10 subjects of the control group were ex-smokers (9 males and 1 female). Their mean age plus or minus standard deviation (SD) was 58.8 plus or minus 15.9 years for the case group and 73.8 plus or minus 10.6 years for the control group. All patients were underwent a careful anamnestic investigation and examination of the oral cavity. After rinsing the mouth with water, each subject put 3 cc of non-stimulated saliva inside a test tube. The saliva was centrifuged and oral peroxidase and superoxide dismutase activity was measured according to a specific assay. Statistical analysis was performed to evaluate differences between the groups and significant differences were observed for p less than 0.05. A significant decrease of GSH-Px activity was detected in the smoking group (p less than 0.05), while the SOD activity was similar in the control and case groups. According to the sex, a significant decrease of GSH-Px activity was noted in males of the smoker group (p less than 0.05), while in the sample of females no significant difference of the enzymatic activity was found. Moreover, among ex-smokers, there was a significant difference in the values of GSH-Px between those who had not smoked for less than ten years and those who had not smoked for more than ten years. Cigarette smoke may alter the detoxification of hydrogen peroxide through a decrease of GSH-Px activity. The overproduction of H2O2 may lead to an oxidative stress that is involved in a large number of diseases, including precancerous and neoplastic lesions of the oral cavity. The effects of cigarette smoke on salivary antioxidant enzymes decrease after withdrawal from smoking and the benefits become more evident with the passage of time.