We previously demonstrated that a depletion of regulatory T (Treg) cells in Lyme arthritis-resistant C57BL/6 mice leads to pathological changes in the tibiotarsal joints following infection with Borrelia burgdorferi. Here, we assessed the effects of Treg cells on the response to B. burgdorferi infection in BALB/c mice, which exhibit infection-dose-dependent disease and a different sequence of immune events than C57BL/6 mice. The depletion of Treg cells prior to infection with 1 × 10², but not 5 × 10³, organisms led to increased swelling of the tibiotarsal joints. However, Treg cell depletion did not significantly affect the development of histopathology at these low doses of infection. BALB/c mice depleted of Treg cells before infection with 1 × 10³ spirochetes harbored a higher borrelial load in the hearts and exhibited higher levels of serum interleukin-10 five weeks later. These results indicate that Treg cells regulate certain aspects of the response to B. burgdorferi in a mouse strain that may display a range of disease severities. As the presentation of Lyme disease may vary among humans, it is necessary to consider multiple animal models to obtain a complete picture of the various means by which Treg cells affect the host response to B. burgdorferi.