Influenza virus infection produces systemic symptoms such as fever, somnolence and fatigue considered as part of the acute phase response (APR) that is regulated in part by cytokines produced by the host acting upon the brain. We have demonstrated viral replication intermediates in the olfactory bulb (OB) of influenza-infected mice as early as 4 h after intranasal inoculation (IN). Consequently, we hypothesized that the presence of the virus will increase the production of cytokines like tumor necrosis factor alpha (TNFa) and interleukin (IL)-1β in this region of the brain. Mature C57BL/6 male mice were inoculated intranasally with a high dose of highly purified PR8 H1N1 influenza virus; boiled virus served as a control. Viral antigen was concentrated in the OB olfactory nerve and glomerular layer of the OB. A significant increase in the number of TNFa immunoreactive (IR) cells was found after a quantitative analysis in the OB external plexiform layer. Double labeling with NeuN demonstrated that neurons in the OB were IR to TNFa. Quantitative analysis of IL-1β IR showed no significant differences in the number of IR cells between infected and control groups. The distribution of the IL-1β IR cells indicates that this cytokine was produced both in OB microglia and neurons. We conclude that there is an increase in the production of cytokines like TNFa in the OB after IN with PR8 influenza virus, which has also been demonstrated in our laboratory with quantitative RT-PCR. These cytokines may be part of the initial signaling to the brain that produces the APR following influenza infection.