Vancomycin-resistant Enterococcus faecium (VRE) is a major cause of antibiotic-resistant infections and thrives in the intestine when colonization resistance is disrupted. Abt et al. report that norovirus infection partially reduces intestinal VRE colonization in mice with antibiotic-induced loss of colonization resistance. Oral resiquimod (R848) — a synthetic molecule that stimulates innate immune antiviral defences — similarly reduced mouse intestinal VRE colonization. R848 activates Toll-like receptor 7 (TLR7) on CD11c+ dendritic cells, to induce interleukin-22 (IL-22) production by innate lymphoid cells and restore ileum expression of the antimicrobial regenerating islet-derived protein 3γ (REG3γ).