Aims: to evaluate changes in clinical periodontal parameters, salivary levels of MMP-8 and MMP-9, in individuals taking Isotretinoin (INN), and compare with individuals not taking the medication and to compare findings among different stages of periodontal disease and healthy periodontium. Material and methods: A case-control study was conducted with a total of 180 human adults divided into six groups. Clinical parameters, including pocket depth (PD), clinical attachment level (CAL), and bleeding on probing (BOP) were measured at six sites per tooth. Whole unstimulated saliva samples were collected from all subjects to detect salivary level of MMP-8, MMP-9 using Enzyme-linked immunosorbent assay (ELISA). Data were analyzed using IBM SPSS Software. Kruskal Wallis test and Mann-Whitney U-tests were used to test any significant differences in any of the groups on all parameters. Pearson Chi-square test was used to compare the distribution of categorical responses across the study groups. All tests were compared at a significance level of 0.05. Results: In Gingivitis cases, INN group was found to have significantly less BOP (P 0.0001). In Periodontitis cases, INN group showed significant difference in BOP (P 0.0001). MMP-8 and MMP-9 were significantly lower among Periodontitis cases taking INN compared to the same group not taking the medication (P 0.0001). Conclusion: INN assists in reducing clinical and biological signs of inflammation related to periodontal disease progression. INN may be a future additive medication to be further evaluated for treating periodontal disease.