Th17 cells are often associated with autoimmunity and been shown to be increased in CD11b(-/-) mice. Here, we examined the role of CD11b in murine collagen-induced arthritis (CIA). C57BL/6 and CD11b(-/-) resistant mice were immunized with type II collagen. CD11b(-/-) mice developed arthritis with early onset, high incidence, and sustained severity compared with C57BL/6 mice. We observed a marked leukocyte infiltration, and histological examinations of the arthritic paws from CD11b(-/-) mice revealed that the cartilage was destroyed in association with strong lymphocytic infiltration. The CD11b deficiency led to enhanced Th17-cell differentiation. CD11b(-/-) dendritic cells (DCs) induced much stronger IL-6 production and hence Th17-cell differentiation than wild-type DCs. Treatment of CD11b(-/-) mice after establishment of the Treg/Th17 balance with an anti-IL-6 receptor mAb significantly suppressed the induction of Th17 cells and reduced arthritis severity. Finally, the severe phenotype of arthritis in CD11b(-/-) mice was rescued by adoptive transfer of CD11b(+) DCs. Taken together, our results indicate that the resistance to CIA in C57BL/6 mice is regulated by CD11b via suppression of IL-6 production leading to reduced Th17-cell differentiation. Therefore, CD11b may represent a susceptibility factor for autoimmunity and could be a target for future therapy.