Serum transfer from arthritic K/BxN mice into naive animals results in arthritis. Mast cells have been shown to be essential since mice lacking these cell type do not develop arthritis upon serum injection. Mast cell function depends on the release of granules filled with mediators such as histamine. Mice deficient in histidine decarboxylase (HDC(-/-)) that do not produce histamine and mice deficient for histamine receptor 1 (H1R(-/-)) or histamine receptor 2 (H2R(-/-)) were injected with arthritogenic sera from the K/BxN mice, and the progression of arthritis was observed through the next 2 weeks. HDC(-/-) mice that are histamine free developed a milder form of arthritis in comparison with the wild-type controls. In both receptor-deficient mice as well as in wild-type controls, the onset and severity of clinical arthritis and ankle thickening occurred during day 1 to 3. These results indicate that histamine is required but not indispensable for the development of serum-induced arthritis and histamine receptors other than those studied here may be involved.