Sleep deprivation is reported to have both beneficial and harmful effects upon host defenses. In the work reported herein, we address the effects of sleep deprivation on the mucosal anti-influenza defenses of both immune and nonimmune BALB/c mice. Sleep deprivation does not depress existing mucosal antiviral defenses in the respiratory tracts of BALB/c mice; in fact, it may actually be beneficial. Nasal mucosal immunity is not adversely affected in immune mice by sleep deprivation. In nonimmune mice, sleep deprivation slows or prevents the progress of nasal influenza viral infection down the trachea into the lungs. By 72 hours post-infection, 12 of 12 control mice shed virus into bronchioalveolar lavages (BAL) while only 2 of 12 sleep deprived mice shed virus (p<0.001). BAL levels of IL-1beta and interferon alpha were increased in sleep deprived animals, suggesting that sleep deprivation may exert its beneficial effects on the respiratory tract by upregulating the production of antiviral cytokines.