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Medical Education 2012: 46: 738-747 Context Medical schools worldwide are increasingly switching to student-centred methods such as problem-based learning (PBL) to foster lifelong self-directed learning (SDL). The cross-cultural applicability of these methods has been questioned because of their Western origins and because education contexts and learning approaches differ across cultures. Objectives This study evaluated PBL's cross-cultural applicability by investigating how it is applied in three medical schools in regions with different cultures in, respectively, East Asia, the Middle East and Western Europe. Specifically, it investigated how students' cultural backgrounds impact on SDL in PBL and how this impact affects students. Methods A qualitative, cross-cultural, comparative case study was conducted in three medical schools. Data were collected through 88 semi-structured, in-depth interviews with Year 1 and 3 students, tutors and key persons involved in PBL, 32 observations of Year 1 and 3 PBL tutorials, document analysis, and contextual information. The data were thematically analysed using the template analysis method. Comparisons were made among the three medical schools and between Year 1 and 3 students across and within the schools. Results The cultural factors of uncertainty and tradition posed a challenge to Middle Eastern students' SDL. Hierarchy posed a challenge to Asian students and achievement impacted on both sets of non-Western students. These factors were less applicable to European students, although the latter did experience some challenges. Several contextual factors inhibited or enhanced SDL across the cases. As students grew used to PBL, SDL skills increased across the cases, albeit to different degrees. Conclusions Although cultural factors can pose a challenge to the application of PBL in non-Western settings, it appears that PBL can be applied in different cultural contexts. However, its globalisation does not postulate uniform processes and outcomes, and culturally sensitive alternatives might be developed. [ABSTRACT FROM AUTHOR]