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Background The UN Refugee Agency has reported that an increasing number of people are being forcibly displaced worldwide. Despite this, global health issues, especially initiatives focusing on physical and psychological conditions of refugees, are still rarely considered in medical curricula. Furthermore, there is little evidence regarding the experiences and possible related psychological strain of medical students who work with refugees. Therefore, the present study aimed to investigate motivations, learning achievements and experiences, as well as psychological strain and possible protective factors, in medical students volunteering in a reception center for refugees. Methods In this prospective study using a mixed-methods approach, we applied (1) qualitative content analysis of semi-standardized interviews in a pre-post design in a subsample of n = 16 students. The aims were to analyze (1a) the students’ motivations and experiences in the reception center, and (1b) the students’ perceived learning achievement. We further administered (2) psychometric questionnaires using a cross-sectional approach to n = 62 students in order to examine (2a) the students’ psychological strain, in terms of secondary traumatization, depression, anxiety and health-related quality of life, and (2b) possible protective factors such as attachment style and sense of coherence. Results The content analysis of the students’ interviews revealed three main categories before the assignment and four main categories subsequently, displaying a broad variety of perspectives. Quantitative analysis identified that 3.2% of the students showed moderate secondary traumatization, and a correlation emerged between the number of shifts and symptom severity of secondary traumatization. The students displayed significantly reduced scores for depression and anxiety, when compared to a sample of first-year medical students. Sense of coherence was identified as a protective factor concerning secondary traumatization. Conclusion A rather small proportion of the medical students working in the reception center displayed explicit symptoms of psychological strain in terms of secondary traumatic stress. Due to their assignments, students were able to improve their cultural awareness, which they reported to be highly relevant for their future occupation. In view of increasing globalization, theoretical and practical courses on issues of flight and global health might therefore be implemented as an obligatory part of medical curricula. Electronic supplementary material The online version of this article (10.1186/s12909-019-1730-8) contains supplementary material, which is available to authorized users.