To investigate the direct role of interleukin (IL) 6 in the development of rheumatoid arthritis, IL-6-deficient (IL-6 −/−) mice were backcrossed for eight generations into C57BL/6 mice, a strain of mice with a genetic background of susceptibility for antigen-induced arthritis (AIA). Both histological and immunological comparisons were made between IL-6-deficient (IL-6 −/−) mice and wild-type (IL-6 +/+) littermates after the induction of AIA. Although all IL-6 +/+ mice developed severe arthritis, only mild arthritis was observed in IL-6 −/− mice. Safranin O staining demonstrated that articular cartilage was well preserved in IL-6 −/− mice, whereas it was destroyed completely in IL-6 +/+ mice. In addition, comparable mRNA expression for both IL-1β and tumor necrosis factor α, but not for IL-6, was detected in the inflamed joints of IL-6 −/− mice, suggesting that IL-6 may play a more crucial role in cartilage destruction than either IL-1β or tumor necrosis factor α. In immunological comparisons, both antigen-specific in vitro proliferative response in lymph node cells and in vivo antibody production were elicited in IL-6 −/− mice, but they were reduced to less than half of that found in IL-6 +/+ mice. Lymph node cells of IL-6 −/− mice produced many more Th2 cytokines than did IL-6 +/+ mice with either antigen-specific or nonspecific stimulation in in vitro culture. Taken together, these results indicate that IL-6 may play a key role in the development of AIA at the inductive as well as the effector phase, and the blockade of IL-6 is possibly beneficial in the treatment of rheumatoid arthritis.