Objectives <p>This prospective cohort study analyzed the effects of systemic retinoic acid use on periodontal status, salivary flow rate (SFR), and salivary and serum levels of interleukin (IL)-1β, IL-8, and monocyte chemoattractant protein (MCP)-1.</p> Materials and methods <p>Twenty-four periodontally healthy participants (13 females, 11 males; aged 18–30 years) were enrolled. Serum and saliva sampling, SFR recordings, and periodontal examination were performed at four different time intervals: before (T0), at the 6th week (T1), at the 5th month (T2), and after the completion (T3) of retinoic acid treatment. Saliva and serum cytokine levels were measured with Luminex assay. Friedman test compared cytokine levels and periodontal parameters between visits. <i>P</i>-values of &lt; 0.05 was considered statistically significant.</p> Results <p>Gingivitis was observed in 33.3% of participants and remained after treatment in 16.7%. Serum IL-8 and MCP-1 levels (<i>p</i> &lt; 0.05) and SFR (<i>p</i> &lt; 0.001) decreased during treatment. Serum MCP-1 reached to its lowest level after treatment (<i>p</i> &lt; 0.05). No significant changes were observed in salivary cytokines or serum IL-1β levels.</p> Conclusion <p>Systemic retinoic acid use is related to increased gingival inflammation, decreased salivary flow, and suppressed systemic chemokine response. These findings suggest that retinoic acid may create a specific risk for individuals prone to develop periodontal diseases.</p> Clinical relevance <p>This research clarifies the potential oral health implications of retinoic acid therapy, which is widely used. This may enable the establishment of specific oral and gingival care protocols tailored for this group of patients. Consequently, timely and evidence-based interventions could help maintain long-term oral health in these patients.</p>