Interleukin-21 (IL-21) is a pleiotropic cytokine, well documented to contribute to the development of Th17 cells which have been shown to play an important role in the pathogenesis of periodontitis. Periodontal disease is a chronic infection of tooth-supporting tissue.This study evaluates the saliva and serum levels of IL-21 in patients with chronic periodontitis and periodontally healthy individuals.The present study was carried out in the Department of Microbiology in association with Department of Oral Medicine and Radiology, Maratha Mandal's N.G.H Institute of Dental Sciences and Research Centre, Belgavi, Karnataka.Fifty samples of each group were included in the present study. The levels of IL-21 were assessed using a commercially available enzyme-linked immunosorbent assay (ELISA) kit and the results were expressed as pg/mL.Statistical analysis was performed using SPSS 17.0 software. Data were expressed as mean ± standard deviation and interquartile ranges and comparison of controls and cases by Mann-Whitney test.Serum and salivary levels of IL-21 were significantly higher in chronic periodontitis group than in controls (P < 0.001). Clinical periodontal parameters correlated positively with serum IL-21 levels.IL-21 is highly expressed in patients with chronic periodontitis and correlated well with clinical parameters of periodontal destruction. Therefore, IL-21 appears to play a role in tissue destruction and can be used as diagnostic biomarker in chronic periodontitis. Saliva can be considered to be a useful alternative to serum as a diagnostic sample.