BACKGROUND: A multi-country, community-based trial on scheduled screening and treatment for malaria in pregnancy was conducted in Benin, The Gambia and Burkina Faso. Despite standardized procedures and outcomes, the study became subject to rumours and accusations of placenta being sold for mystical and financial gain by trial staff, leading to drop-out rates of 30% and the consequent halting of placental biopsy sampling in Benin. This paper explores the role of socio-cultural beliefs related to placenta and identified additional factors contributing these rumours. METHODS: A qualitative comparative emergent-theory design was used to assess social factors related to trial implementation and uptake in the three countries. Data from participant observation, informal conversations, group discussions and interviews were triangulated and analysed with NVivo Qualitative Analysis software. RESULTS: Despite similar sociocultural beliefs about the sacred nature of the placenta in all three study countries, these beliefs did not affect participation rates in Burkina Faso and The Gambia and placenta-related rumours only emerged in Benin. Therefore, the presence of beliefs is not a sufficient condition to have generated placenta-selling fears. The rumours in Benin reflected the confluence of placenta-related beliefs and factors related to the implementation of the trial (including a catalysing adverse event and miscommunication during the informed consent procedure). Furthermore, distinct socio-political factors contributed to the emergence of rumours, including the historical distrust in governmental organizations and the tense relationship between some of the actors involved in the trial. CONCLUSION: Transdisciplinary social science research designs should accompany the implementation of the trial. The integration of multiple stakeholders' knowledge and involvement is required to define and solve upcoming barriers.