Sterol metabolites are known to be associated with immune responses. 25-Hydroxycholesterol (25HC) is a cholesterol metabolite that is produced by macrophages. The production of 25HC was reported to be TLR-dependent, indicating the involvement of 25HC in innate immunity. Now Blanc et al. show that macrophages synthesize 25HC to exert an antiviral effect. STAT1 was shown to be the most essential transcriptional factor involved in the induction of cholesterol 25-hydroxylase (Ch25h), the enzyme required to produce 25HC, indicating the importance of STAT1 in oxysterol-mediated innate immunity.