Tumor necrosis factor–α (TNF-α) is a major mediator of both acute and chronic inflammatory responses in many diseases. Tristetraprolin (TTP), the prototype of a class of Cys-Cys-Cys-His (CCCH) zinc finger proteins, inhibited TNF-α production from macrophages by destabilizing its messenger RNA. This effect appeared to result from direct TTP binding to the AU-rich element of the TNF-α messenger RNA. TTP is a cytosolic protein in these cells, and its biosynthesis was induced by the same agents that stimulate TNF-α production, including TNF-α itself. These findings identify TTP as a component of a negative feedback loop that interferes with TNF-α production by destabilizing its messenger RNA. This pathway represents a potential target for anti–TNF-α therapies.