Mice lacking Toll-like receptor 4 (TLR4) have previously been shown to be highly refractory to influenza-induced mortality. Shirey et al. now show that the synthetic TLR4 antagonist eritoran (also known as E-5564; Eisai) prevents lethality in influenza-infected mice and significantly reduces lung pathology, clinical symptoms and viral titres, even when administered as late as 6 days after infection. Furthermore, the drug blocks the production of cytokines and oxidized phospholipids, which are associated with influenza-induced inflammation. Together with the favourable safety profile of the drug, these data indicate that eritoran could represent a novel therapeutic strategy for influenza infections.