Forkhead transcription factors play key roles in the regulation of immune responses. Here, we identify a role for one member of this family, Foxj1, in the regulation of T cell activation and autoreactivity. Foxj1 deficiency resulted in multiorgan systemic inflammation, exaggerated Th1 cytokine production, and T cell proliferation in autologous mixed lymphocyte reactions. Foxj1 suppressed NF-κB transcription activity in vitro, and Foxj1-deficient T cells possessed increased NF-κB activity in vivo, correlating with the ability of Foxj1 to regulate IκB proteins, particularly IκBβ. Thus, Foxj1 likely modulates inflammatory reactions and prevents autoimmunity by antagonizing proinflammatory transcriptional activities. These results suggest a potentially general role for forkhead genes in the enforcement of lymphocyte quiescence.