Although natural killer (NK) cells have been implicated in regulating immune responses, their ability to modulate disease development in autoimmune arthritis has not been analyzed. Here we investigate the contribution of NK cells to regulating collagen-induced arthritis, a well-characterized preclinical model of human rheumatoid arthritis. We find that the disease is induced by the combined action of two CD4 + T helper (T H) subsets: follicular T H cells and T H17 cells. Both CD4 + T H subsets are highly susceptible to lysis by NK cells after activation. Administration of antibody that activates NK cells through blockade of its inhibitory CD94/NKG2A receptor allows enhanced elimination of pathogenic follicular T H and T H17 cells and arrest of disease progression. These results suggest that antibody- dependent enhancement of NK activity may yield effective, previously undescribed therapeutic approaches to this autoimmune disorder.