Borrelia burgdoiferi-induced disease susceptibility was explored in disease-resistant C57/BL6 (B6) and -susceptible C3H/He (C3H) mice with and without the beige (bg) mutation, which is associated with granulocyte and NK cell dysfunction. Both B6 and C3H mice had more prevalent and severe arthritis than their congenic partners, and B6-bg mice developed arthritis equal in severity to that in C3H mice. Spirochetes were visualized in joint tissue of B6-bg mice but not B6 mice. No differences in spirochete isolation from tissues or immunoglobulin titers to B. burgdorferi were noted between groups. Depletion of granulocytes with cyclophosphamide and macrophages with silica in B6 and C3H mice modified arthritis susceptibility, but depletion of NK cells by serotherapy in B6 mice had no effect on disease. This study demonstrates that innate genetic resistance to Lyme arthritis in mice can be overcome by a single gene mutation, which is probably mediated through granulocyte function.