The resistance of an experimental sealer (KT-308) to bacterial ingress was assessed in six beagle dogs. In four mandibular premolars per dog, canals were prepared, filled with condensed gutta-percha and either KT-308 or Roth 801 cement (n = 24 roots), and the pulp chambers inoculated with plaque. Two additional premolars per dog were similarly root-filled, but not inoculated (n = 12 and 11, respectively). One incisor per dog was inoculated, but not root-filled (n = 6). Dogs were terminated after 6 months, and jaw blocks were retrieved and processed for light microscopic examination of the periapical tissues. Inflammation about the inoculated roots was significantly lower (p < 0.03) for KT-308 (17%) than Roth 801 cement (46%). Inflammation about the noninoculated roots did not differ significantly between KT-308 (8%) and Roth 801 cement (36%). This study demonstrated a better functional efficacy of KT-308 than of Roth 801 cement, and validated this in vivo model for assessment of root filling materials.