TIA-1 and TIAR are related proteins that bind to an AU-rich element (ARE) in the 3′ untranslated region of tumor necrosis factor alpha (TNF-α) transcripts. To determine the functional significance of this interaction, we used homologous recombination to produce mutant mice lacking TIA-1. Although lipopolysaccharide (LPS)-stimulated macrophages derived from wild-type and TIA-1–/– mice express similar amounts of TNF-α transcripts, macrophages lacking TIA-1 produce significantly more TNF-α protein than wild-type controls. The half-life of TNF-α transcripts is similar in wild-type and TIA-1–/– macrophages, indicating that TIA-1 does not regulate transcript stability. Rather, the absence of TIA-1 significantly increases the proportion of TNF-α transcripts that associate with polysomes, suggesting that TIA-1 normally functions as a translational silencer. TIA-1 does not appear to regulate the production of interleukin 1β, granulocyte–macrophage colony-stimulating factor or interferon γ, indicating that its effects are, at least partially, transcript specific. Mice lacking TIA-1 are hypersensitive to the toxic effects of LPS, indicating that this translational control pathway may regulate the organismal response to microbial stress.