OBJECTIVES: Appraise the effect of systemic Paeoniflorin (Pae) application on the periodontium during and after induction of experimental periodontitis in the presence of ligature and after its removal. DESIGN: Seventy male Wistar rats were separated into seven equal groups. The first group was reserved as healthy control group (Group 1: no periodontitis, no medication) and experimental periodontitis was induced with ligature in the remaining rats. In experimental periodontitis groups, Pae or saline was administered systemically in three differet periods; during the experimental periodontitis induction (period 1), after experimental periodontitis induction which ligature removed (period 2) or ligature kept in position (period 3). Only, one of the groups acted as the control periodontitis group and received no treatment. Experimental periodontitis groups were as follows; Group 2: medication in period 1, Group 3: periodontitis and no medication, Group 4: medication in period 2, Group 5: saline application in period 2, Group 6: medication in period 3, Group 7: saline application in period 3. Matrix metalloproteinases-9 (MMP-9) levels and interleukin-10 (IL-10) levels were detected biochemically and histomorphometric analyses were performed. These analyses included measurements of the area of alveolar bone, the level of alveolar bone, and attachment loss. RESULTS: Area of alveolar bone and IL-10 levels were higher in the Pae-administered groups; level of alveolar bone, attachment loss, and MMP-9 levels were correspondingly lower (P < 0.05). The beneficial effects at histomorphometrical and biochemical levels of Pae were the strongest in the rats that were administered Pae after the removal of ligature. CONCLUSIONS: Systemically administered Pae had a positive effect on the healing of periodontal tissues. Pae can be used as a new therapeutic agent for periodontal diseases, but microbiology-based studies and more extensive biochemistry-based experimental and clinical studies are needed to address this possibility.