We report two cases of Mycobacterium simiae infections differing by the site of infection, the immunological status of the patients and the diagnostic methods used. The first case is a disseminated infection in an advanced immunosuppressed patient who died quickly confirming the severity of this infection in the context of HIV infection. The second case presented is a respiratory disease in a women with a past history of tuberculosis and an uneventful evolution of the M. simiae infection under treatment. These two cases demontrate the importance of molecular methods to correctly identify M. simiae.