Background:Tobacco use is a harmful habit that causes adverse effects on oral health and plays a most important role in cancer development. Saliva is the first fluid that is exposed to tobacco and its antioxidant system plays an important role in anti-cancer potential; therefore, this study was designed to compare the antioxidant activity and immunologic system of saliva in tobacco users (smokers and smokeless tobacco users) and non-users.Materials and Methods:In this cross-sectional study, unstimulated saliva samples of 75 healthy individuals from three equal groups were investigated. Participants in group A had no periodontal disease and never smoked. Group B had no periodontal disease, never used smokeless tobacco, but had 3 years history of smoking at least 10 cigarettes daily. The twenty-five participants in group C had no periodontal disease and had 1 year history of chewing a 10-g tobacco packet daily. Activity of salivary superoxide dismutase (SOD), salivary glutathione peroxide, and salivary IgA concentration was evaluated. Data were analyzed using SPSS (version 18) and running Kruskal-Wallis test. Statistical significance was set at p<0.05.Results:There were significant differences in the activities of the two enzymes and salivary IgA levels among the three groups. Activity of glutathione peroxide was higher in smokeless tobacco users. (P<0.001) while that of superoxide dismutase was higher in non-tobacco users than users (P<0.001). Salivary IgA levels were higher among smokeless tobacco users (p=0.04).Conclusion:Based on the results of the present study, the use of tobacco products decreases the antioxidative activity of the saliva and increases salivary IgA levels at the same time.