Studies have shown that co-infection of influenza viruses with bacteria is an important cause of high mortality during the epidemic of influenza.There are at least 12 species of bacteria that have been reported to be able to co-infect with influenza.Among those species,co-infection with Staphylococcus aureus is not only the most common but also the most lethal.However,the pathogenesis of high mortality from co-infection with influenza virus/S.aureus remains elusive.In addition,co-infection of influenza virus/S.aureus can induce severe pneumonia.There is new evidence that influenza virus can reduce the host′s tolerance to pathogenic or inflammatory injury,and the two pathogens can also synergistically aggravate toxic effects on the host.Here,we review the mechanisms of severe mortality of influenza infection associated with S.aureus co-infections in order to contribute to prevention and control of influenza in the future.