Invasion and persistence of the neuroadapted influenza virus A/WSN/33 in the mouse olfactory system was studied. WSN/33 instilled intranasally infected neurons in the olfactory epithelium and was transported in axons to the olfactory bulbs in wild type mice that survived the infection. In adult mice lacking the recombination activating gene 1 (RAG-1-/-), infected neurons occurred in the olfactory bulbs for 22-65 days after which the mice developed a rapidly progressive lethal infection affecting neurons in olfactory projection pathways, i.e. primary olfactory cortex, raphe in upper brainstem and hypothalamus. Adult mice without genes for interferon (IFN)-alpha/beta receptor, IFN-gamma receptor, inducible nitric oxide synthase (iNOS), IgH, the transporter associated with antigen processing 1 (TAP1), and natural killer cell-depleted mice, all survived the infection. Viral RNA was found in the olfactory bulbs in more than 80 per cent of the surviving iNOS-/-, IFN-gamma receptor-/-, and TAP1-/- mice. Taken together, this study shows that influenza A virus can invade the brain through the olfactory pathways and that the cellular immune responses prevent establishment of persistent infections in the olfactory bulbs. Furthermore, innate responses in olfactory bulbs may for a period of time keep the infection under control.