The nonapoptotic functions of Fas ligation are incompletely characterized. In contrast to expectations, we show here that Fas-deficient mice developed less-severe collagen-induced arthritis than did control mice. Despite having milder arthritis, Fas-deficient mice had more of the critical pro-inflammatory mediator interleukin-1β (IL-1β) in their joints, suggesting inefficient activation through IL-1 receptor 1 (IL-1R1) when Fas signaling is deficient. In primary human macrophages and macrophages from Fas- or Fas ligand (FasL)-deficient mice, interruption of Fas-FasL signaling suppressed nuclear factor-κB activation and cytokine expression induced by IL-1β and lipopolysaccharide. This cross-talk was mediated by the Fas-associated death domain through interaction with myeloid differentiation factor 88. These observations document a unique mechanism whereby Fas-FasL interactions enhance activation through the IL-1R1 or Toll-like receptor 4 pathway, which may contribute to the pathogenesis of chronic arthritis.