Tissue reaction to gutta-percha was studied using subcutaneously implanted Teflon cages in guinea pigs. Gutta-percha was tested in three forms: (i) as large particles prepared by dividing gutta-percha cones into pieces, (ii) as fine particles prepared by ball-milling of gutta-percha, and (iii) as particles produced by dissolving gutta-percha in rosin-chloroform. Gutta-percha evoked two distinct types of tissue response. The large pieces were well encapsulated and the surrounding tissue was free of inflammation. The fine particles evoked an intense, localized tissue response, characterized by the presence of macrophages and multinucleated giant cells. The rosin-chloroform treated gutta-percha induced a similar tissue reaction to that observed with the fine particles of gutta-percha. In addition, cell remnants were present in association with the material, which indicates an initial toxicity to rosin-chloroform treated gutta-percha. These results show that the size and surface character of gutta-percha can determine the type of tissue reaction to the material. The accumulation of macrophages around gutta-percha may be an important factor in the impairment of healing of periapical lesions when teeth are root filled with excess material.