Significance Anti-cytokine therapy has revolutionized the treatment of autoimmune diseases. However, recent data suggest that cytokines, in particular TNF, produced by various cell types may play distinct and sometimes opposite roles in the inflammatory responses. In certain autoimmune diseases TNF produced by monocytes and macrophages plays a pathogenic role, whereas TNF produced by T cells may be protective. In addition, T-cell–derived TNF is indispensable for resistance to infections, such as tuberculosis. To demonstrate that cell-type–restricted anti-cytokine therapy may be advantageous, we generated bispecific antibodies that neutralize TNF produced by myeloid cells. Cell-targeted inhibition of TNF is more effective than systemic TNF ablation in protecting mice from TNF-mediated hepatotoxicity. This provides a rationale for the development of novel anti-TNF agents.