Methods: 10 healthy Mongrel dogs were used in these studies. Immunologic responses were analyzed for antibody responses(Stavisky ) and cell mediated immunity-lymphocyte stimulation (Bach ).Immunization occurred via 20 root canals over a 28 day period in 5 dogs.In 5 other dogs, endodontics was performed on 5 teeth per dog , using ZOE containing C-14 labelled 6.5% paraformaldehyde paste.In each animal, the radioactivity was measured over 1 hr. 1, 7,14,21,and 28 days in the blood,biopsy specimens of the submandibular lymph nodes, kidney, and liver. At 28 days, all the animals were sacrificed.The teeth and the surrounding bone were processed for light microscopy . Semiserial sections ( 5-8 microns), stained with hematoxlin and eosin, and examined in diffuse and polarized light.The sections were evaluated for: the occurrence of acute and chronic infammatory cells, foreign body cells, extravasated,disintegrating erythrocytes, the occurrence of brown pigment, the presence and location of tissue disintegration products, and the location of paste particles in the cells, vessels and tissues. Results: 1)Pulp altered by 6.5% paraformaldehyde -ZOE paste produced specific antibody and cell mediated responses over a 28 day period in dogs.2)When dog root canals were obturated with C-14 labelled paraformaldehyde-ZOE paste within the confines of the canal, the radioactivity was detected in the blood, submandibular lymph nodes, kidney and liver over 28 days .3)Histopathologic evaluation demonstrated periapical tissue,cell, vessel, bone inflammation and damage adjacent to the paste material.Polarized light was used to verify the presence of paste material in the cells and vessels. Conclusions: The use of ZOE containing paraformaldehyde paste should not be used in endodontics. (This paper is a tribute to Dr. Langeland who passed away this past year)