Here we showed, for a replication-competent HAdV type of medical importance, that tetraspanin CD9-, CD63- and CD81-positive small EVs released by infected lung epithelial cells at a pre-lytic early stage during infection carry the viral genome, select structural and non-structural viral proteins and VA RNAs providing a vehicle for protected cell-to-cell dissemination of the HAdV infection. Here, CD63 is linked to infection.