BackgroundWhile Ghana has a good track record in the Expanded Programme on Immunization, there are substantial challenges with regards to subsequent vaccinations, particularly after the first year of life of the child. Given that the last dose of the RTS, S/AS01E vaccine against malaria is administered at 24 months, there is a high likelihood of default. Hence, it is imperative to understand the dynamics and reasons for the defaults to enable the development of effective implementation strategies. This study explored why caregivers default on the RTS, S/AS01E vaccine from the perspective of health service providers and caregivers.MethodsThis study employed an exploratory, descriptive approach. Using a purposive sampling technique, caregivers who defaulted and health service providers directly involved in the planning and delivery of the RTS, S/AS01E vaccine at the district level were recruited. A total of five health service providers and 30 mothers (six per FGD) participated in this study. Data analysis was done using NVivo-12 following Collaizi’s thematic framework for qualitative analysis. The study relies on the Standards for Reporting Qualitative Research.ResultsReasons for defaulting included the overlap of timing of the last dose and the child starting school, disrespectful attitudes of some health service providers, concerns about adverse side effects and discomforts, travel out of the implementing district, the perception that the vaccines are too many, and lack of support from partners.ConclusionTo reduce the occurrence of defaulting on the RTS, S/AS01E vaccine programme, stakeholders must reconsider the timing of the last dose of the vaccine. The schedule of the RTS, S/AS01E vaccine should be aligned with the established EPI schedule of Ghana. This will significantly limit the potential of defaults, particularly for the last dose. Also, the findings from this study underscore a need to encourage male partner involvement in the RTS, S/AS01E vaccine programme. Health promotion programmes could be implemented to raise caregivers’ awareness of potential adverse reactions and discomforts—this is necessary to prepare the caregiver for the vaccine process psychologically.