The contribution of the spleen to the arthritogenic and immune response to type II collagen in mice was measured by a series of in vitro and in vivo experiments. Negligible antibody production and proliferative responses to collagen were measured in the spleen from immunized mice, compared to lymph node and peripheral blood. Further, splenectomized mice were found to be susceptible to collagen induced arthritis with a similar disease incidence to sham operated controls. There were no major differences in the sera antibody responses or the delayed-type hypersensitivity responses to collagen between the splenectomized and control mice. The primary regulation of the response to type II collagen in collagen induced arthritis was apparently independent of the spleen cell population.