BACKGROUND: Vaccination coverage remains suboptimal in many parts of the world, especially in low-and middle-income countries (LMICs), including South Africa. Vaccine hesitancy, a recognized factor contributing to low vaccination uptake in many parts of the world, is suspect in the suboptimal vaccination coverage level in South Africa, particularly in the Western Cape Province. We aimed to investigate vaccine hesitancy and to describe point-of-care vaccinators' perceptions of the drivers of vaccine hesitancy in the Cape Metropolitan District, South Africa (Cape Metro). We conducted in-depth interviews with 19 point-of-care vaccinators in 16 purposively selected healthcare facilities in the Cape Metro between September and November 2019. Participants were sampled purposively as 'rich cases' who had been delivering vaccination services for at least five years post-qualification. We organized the data thematically in ATLAS.ti and report findings thematically by the types of reasons participants reported for vaccine hesitancy amongst clients. FINDINGS: Of the 19 interviewees, 11 (59%) reported having encountered vaccine-hesitant clients at some point in their careers. Reasons reported for vaccine hesitancy by clients included: (a) religion, (b) internet misinformation, (c) concern over causing the child pain, (d) natural immunity development, and (e) concern about possible adverse effect following immunization. Vaccine hesitancy in the Cape Metro cuts across all socio-economic classes. Also, some communities perceived to be vaccine-hesitant were mentioned by the participants in this study. CONCLUSIONS: Attitude towards vaccination are generally positive in the Cape Metro. However, vaccine hesitancy is present. The issues of vaccine hesitancy at the reported levels can still be mitigated by continuous health education in the clinics and communities, as well as stakeholder engagement as suggested by the point-of-care vaccinators in the Cape Metro.