Considerable effort has been made to elucidate the mechanism of Lyme arthritis. We focused on p19, a cell cycle-regulating molecule, because it is known to inhibit cell cycle division of T lymphocytes which may be responsible for the induction of arthritis. We show that anti-p19 antibody treatment enhances the inflammatory response normally detected at the tibiotarsal joints of Borrelia burgdorferi-vaccinated and Borrelia bissettii-challenged mice. Specifically, anti-p19 antibody treatment augmented the severity of inflammation within the synovial and subsynovial tissue. Moreover, treatment with anti-p19 antibody caused severe erosion of cartilage and bone with ankle joint destruction. In addition, anti-p19 antibody treatment of Borrelia-vaccinated and -challenged mice enhanced the borreliacidal antibody response, especially against the vaccine isolate. The novel activities of anti-p19 antibody show that p19 may be an important therapeutic site for the treatment of Lyme arthritis.