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Objective: The objective of this systematic analysis was to perform a qualitative and quantitative synthesis of the literature concerning salivary and serum leptin variations in patients with chronic periodontitis (CP) compared with healthy subjects. Saliva leptin concentration analysis could be a relevant and non-invasive biological test for the evaluation of periodontal disease in both medical and clinical trials, beyond the clinical and radiographic elements. Material and Method: Querying the PubMed and Web of Science databases identified articles that met our inclusion criteria. Quantitative analysis of the literature data was performed with the Review Manager 5.3 software. Results: The qualitative analysis included 14 articles and showed a decrease of salivary leptin (5 studies out of 5) and an increase of serum leptin (11 of 12 studies) in patients with CP compared to unaffected subjects of CP. Quantitative analysis was performed on 4 trials. For salivary leptin, we confirmed a decrease in its level in patients with CP with a standardized mean difference (SMD) of −2.27, 95% CI [−2.68, −1.86]. The difference was highly significant but we detected a very important heterogeneity in this dataset (I2 = 94%). For serum leptin, we also confirmed an increase in its rate in patients with CP with an SMD of 2.18, 95% CI [1.75, 2.61]. The difference was highly significant but the heterogeneity measured in this dataset was also too high (I2 = 95%). Conclusion: The current level of evidence was insufficient to assert an increase in serum leptin and a decrease in salivary leptin in CP patients compared to healthy controls due to a great heterogeneity of the values measured in the studies.