Sleepiness is a common perception during viral infection. Nevertheless, very little is known about the effects of viral infection on sleep. The aim of the present study was to test whether sleep was altered by influenza viral infection in mice. After 2-3 days of baseline sleep recordings, Swiss-Webster mice were infected intranasally with a lethal (H1N1) or a nonlethal (H3N2) strain of influenza virus. Sleep was recorded again for an additional 3 days. Non-rapid eye movement sleep (NREMS) was dramatically increased after inoculation of the H1N1 virus with a latency about 16 hr. Rapid eye movement sleep (REMS) was significantly suppressed after a long latency. Both changes lasted until the end of the recording and occurred in both young (35-day-old) and adult (90- to 100-day-old) animals. Control animals did not show changes in sleep after sham infection with allantoic fluid. The H1N1 virus also caused dramatic decreases in body temperature and locomotor activities with a latency about 4-5 hr after viral inoculation. The H3N2 virus induced very similar changes in sleep, although the effects were much smaller in magnitude than those induced by the H1N1 virus, even though a much higher dose (10-fold) of the H3N2 virus was used. The present study shows that influenza viral infection induces profound and long-lasting increase of NREMS and suppression of REMS. These viral-induced changes in sleep likely represent a host-defense response.