Numerous compounds have been used as root-end filling materials. Based on the results of in vitro and intraosseous implantation tests, mineral trioxide aggregate (MTA) seems to have potential as a root-end filling material. The purpose of this study was to examine the periradicular tissue response of dogs to MTA and amalgam. Lesions were developed in periradicular tissues of 46 roots in six beagle dogs. The canals on half of the roots were instrumented and obturated with gutta-percha and sealer, and their access cavities were sealed with MTA. The remaining root canals were instrumented and obturated with gutta-percha and sealer, and their access cavities were sealed with MTA. The remaining root canals were instrumented and obturated with gutta-percha without root canal sealer. The access cavities of the teeth in this group were left open to the oral cavity. After surgical resection of roots, half of the root-end cavities were filled with amalgam and the rest with MTA. The periradicular tissue response of the dogs was evaluated histologically 2 to 5 and 10 to 18 wk following periradicular surgery. Statistical analysis of the results showed less periradicular inflammation and more fibrous capsules adjacent to MTA, compared with amalgam. In addition, the presence of cementum on the surface of MTA was a frequent finding. The results show that MTA can be used as a root-end filling material.