Interpreters and mediators working in complex humanitarian settings are faced with new challenges, both linguistic and non-linguistic. As part of on-going research, this chapter reports on cultural differences in interpreting major variables in interpreter-mediated medical encounters in complex humanitarian scenarios. The author will address the importance of cultural issues in humanitarian interpreting, based on the assumption that differences in culture can be a serious barrier to effective humanitarian communication. The author focuses on the interpreters and cultural mediators working for the Italian NGO Emergency ONG Onlus, which provides medical assistance to migrant communities in Southern Italy at its Castel Volturno clinic. The aim is to highlight the importance of a shared culture between interpreters/mediators and their clients and adequately deal with existing cultural differences in order to enact a so-called “cultural compromise” between migrant patients and health professionals with the goal to facilitate prevention, health promotion and education, and treatment.