The development of experimental Lyme arthritis has been correlated with the expression of a number of chemokines and cytokines, however, none of these have been measured directly from the arthritic joint. We examined the temporal expression of IL-1β, IL-4, IL-6, IL-10, IL-12p70, GM-CSF, IFN-γ, TNF-α, macrophage inflammatory protein-2, KC, macrophage inflammatory protein-1α, and monocyte chemoattractant protein-1 directly from the tibiotarsal joint in arthritis-resistant C57BL/6 (B6) and-susceptible C3H/He (C3H) mice. Only the chemokines KC and monocyte chemoattractant protein-1 were differentially expressed in joints of B6 and C3H mice and correlated with the development of Lyme arthritis. Infection of CXCR2−/− mice on either genetic background resulted in a significant decrease in the development of pathology, although infection of CCR2−/− mice had little or no effect. Neutrophils in CXCR2−/− mice were marginalized within blood vessels and could not enter the joint tissue. These results suggest that chemokine-mediated recruitment of neutrophils into the infected joint is a key requirement for the development of experimental Lyme arthritis.