Aim: This study aimed to assess the effects of smoking on systemic and local oxidative stress markers in patients with periodontitis. Methods: A total of 72 patients with periodontitis [38 smokers (S +P+), 34 non-smokers (S-P+)] and 54 periodontally healthy individuals [28 smokers (S+P-), 26 non-smokers (S-P-, control)] were included. After clinical measurements and samplings, the cotinine level, total antioxidant capacity (TAOC), total oxidative status (TOS), and malondialdehyde (MDA) level in the serum and saliva were determined, and the oxidative stress index (OSI) was calculated. Kruskal-Wallis and Mann-Whitney U tests were used for multiple and pairwise comparisons. Correlations were analyzed using Pearson correlation coefficient. P<0.05 was considered statistically significant. Results: Smoking and periodontitis decreased the serum and salivary TAOCs and increased the TOS, MDA level, and OSI. The smokers with periodontitis had the lowest TAOC and the highest TOS, MDA level, and OSI, while the controls had the highest TAOC and the lowest TOS, MDA level, and OSI. The systemic and local effects of smoking seemed more pronounced than those of periodontitis in the oxidative stress study, but no significant difference was identified between the smoking (S+P-) and periodontitis (S-P+) groups. The clinical parameters and oxidative stress markers showed both substantial positive and negative relationships in all groups (p<0.01). Conclusions: It can be concluded that smoking and periodontitis (S+P+) are associated with a decrease in serum and salivary TAOCs and an increase in TOS, MDA levels, and OSI. Smoking has a similar effect as periodontitis on local and systemic oxidative stress, and oxidative stress caused by smoking may be a significant factor in the pathophysiology of periodontitis.