Objective: The multifunctional cytokine interleukin-6 (IL-6) has actions on multiple cell types, including promotion of the development of immune cells and osteoclasts. Periapical inflammation as the result of root canal infection is characterized by the accumulation of inflammatory cells and bone resorption. The effect of IL-6 on periapical lesion formation after pulpal infection is unknown. We sought to determine whether deletion of IL-6 affects periapical lesion formation after pulp exposure. Methods: Molar pulps of homozygous IL-6 knock-out mice (IL-6–/–, strain B6, 129-Il6tm1Koe ) and wild-type mice (IL-6+/+) were exposed, and the mice were killed at 1, 2, 3, 5, and 8 weeks after the exposure. Mouse jaws were decalcified and prepared for histologic examination of periapical lesions. Results: The IL-6–/– mice developed larger periapical lesions more rapidly than did the IL-6+/+ mice. Conclusions: IL-6 deletion promoted periapical lesion development.(Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;92:83-8)