We have investigated the role of the activation of nuclear poly(ADP-ribose) polymerase (PARP) enzyme, a mediator of downstream nitric oxide toxicity, using a combined approach of pharmacological inhibition and genetic disruption in a ligature-induced-periodontitis model in rats and mice. Immunohistochemical analysis revealed significantly increased poly(ADP-ribose) nuclear staining (indicative of PARP activation) in the subepithelial connective tissue of the ligated side compared with the non-ligated side. Ligation-induced periodontitis resulted in marked plasma extravasation in the gingivomucosal tissue and led to alveolar bone destruction compared with the non-ligated side, as measured by the Evans blue technique and by videomicroscopy, respectively. PARP inhibition with PJ34, as well as genetic PARP-1 deficiency, significantly reduced the extravasation and the alveolar bone resorption of the ligated side compared with controls. Thus, PARP activation contributes to the development of periodontal injury. Inhibition of PARP may represent a novel host response modulatory approach for the therapy of periodontitis.