Collagen type II (CII)-induced arthritis (CIA) in mice is a model for rheumatoid arthritis (RA) in which the role of T lymphocytes remains controversial. To clarify this, we have bred a targeted gene deletion of TCR β or δ loci into two mouse strains susceptible to CIA, the B10.Q and DBA/1 strains. The TCRβ^–/– mice lacked αβ T cells, which was compensated by an expansion of B cells, γδ T cells and NK cells. The β^–/– mice, but not control β^+/– littermates, were completely resistant to CIA. The production of anti-CII IgG antibodies was also abolished in β^–/– mice, revealing a strict αβ T cell dependency. In contrast, β^–/– mice produced reduced, but significant, anti-CII IgM titers after immunization with either CII or ovalbumin, indicating a multispecificity for these αβ T cell-independent IgM antibodies. The TCRδ^–/– mice lacked γδ T cells but had no other significant changes in lymphocyte or monocyte subsets. The cytokine response (IL-2, IL-4, IL-10 and IFN-γ) in δ^–/– mice, quantified by flow cytometry staining of mitogen-stimulated lymphocytes, was indistinguishable from normal mice. Likewise, no statistically significant differences were observed in CIA between mice lacking γδ T cells and control littermates, considering arthritis incidence, day of disease onset, maximum arthritic score, anti-CII IgG titers and disease course. We conclude that αβ T cells are necessary for CIA development and for an IgG response towards CII, whereas γδ T cells are neither necessary nor sufficient for development of CIA.