Abstract Aim This cross‐sectional case–control study was designed to determine the association of the salivary concentration of CD 9/ CD 81 exosome‐related tetraspanins with the periodontal clinical status. Materials and Methods Saliva samples from 104 periodontitis patients and 45 healthy controls were collected. Periodontal status was assessed based on full‐mouth clinico‐radiographical data, and salivary concentration of the analytes was calculated by ELISA . The association between the biomarkers with disease status was analysed using multivariate binary logistic regression models. Results Significantly decreased salivary levels of CD 9 and CD 81 exosomes were detected in periodontitis patients in comparison with healthy controls. Also, negative significant correlations between salivary concentrations of CD 9/ CD 81 exosomes regarding clinical measurements were observed. Likewise, a significant downward trend of the concentration of these two biomarkers concerning the stage and grade of disease could be identified. Logistic regression analyses revealed a strong/independent association for decreased salivary concentration of CD 81 exosomes regarding disease status. Confounding and interaction effects between age and salivary concentration of CD 9 exosomes were also noted. Conclusion Reduced salivary concentration of CD 9/ CD 81 exosomes might be of significance in the context of periodontal disease pathogenesis.