In the murine model of Lyme disease, C3H/He mice exhibit severe arthritis while C57BL/6N mice exhibit mild lesions when infected withBorrelia burgdorferi. Joint tissues from these two strains of mice harbor similar concentrations of B. burgdorferi, suggesting that the difference in disease severity reflects differences in the magnitude of the inflammatory response to B. burgdorferi lipoproteins. Stimulation of bone marrow macrophages from C3H/HeN mice with the B. burgdorferi lipoprotein OspA resulted in higher-level production of the inflammatory mediators tumor necrosis factor alpha, nitric oxide, and interleukin-6 (IL-6) than that of macrophages from C57BL/6N mice. In contrast, macrophages from C57BL/6N mice consistently produced larger amounts of the anti-inflammatory cytokine IL-10 than did C3H/HeN macrophages. Addition of recombinant IL-10 suppressed the production of inflammatory mediators by macrophages from both strains. IL-10 was found to modulateB. burgdorferi-induced inflammation in vivo, since C57BL/6J mice deficient in IL-10 (IL-10^−/−) developed more severe arthritis than wild-type C57BL/6J mice. The increase in arthritis severity was associated with a 10-fold decrease in the number ofB. burgdorferi organisms present in ankle tissues from IL-10^−/− mice. These findings suggest that in C57BL/6 mice, IL-10-dependent regulation of arthritis severity occurs at the expense of effective control of bacterial numbers.