Lyme disease represents a complex response to Borrelia burgdorferi that involves both bacterial factors as well as host responses. This results in an inflammatory reaction at several sites, including the synovial lining of joints. Synovial tissues of inflamed joints contain cells expressing high levels of Fas and Fas ligand (FasL). Although Fas stimulation is typically associated with cell death, it can also transmit stimulatory signals to certain cell types. Among these are dendritic cells and macrophages, which are abundant in inflamed synovium. To better assess the role of FasL in the pathogenesis of Lyme arthritis, we evaluated the response to B. burgdorferi infection in C3H/HeJgld mice that bear a nonfunctional mutation in FasL. Compared to wild-type C3H+/+ mice, C3Hgld mice had a similar bacterial burden and antibody response 2 weeks and 4 weeks following infection, but they manifested a significantly reduced Borrelia-specific cytokine response. In addition, C3Hgld mice developed a greatly reduced incidence and severity of arthritis. The findings document a contribution of FasL to the host inflammatory response to B. burgdorferi.