This article explores the global challenge of vaccine hesitancy in Brazil and South Africa, two socioeconomically unequal BRICS nations, through a socio-anthropological lens. Also, both Brazil and South Africa are multiracial nations where ethnicity still defines social positions reflected in patterns of illness and death. Despite established immunization programs, both countries face coverage decreases leading to disease outbreaks. This qualitative study aims to understand childhood vaccine hesitancy in these contexts, highlighting social and behavioral drivers. In-depth interviews were conducted in three cities: Sao Luis (Maranhao State, Brazil), Florianopolis (Santa Catarina State, Brazil) and Cape Town (Western Cape Province, South Africa). Families with children up to 6 years old were included. Data were analyzed using thematic analysis methods. Forty-two caregivers in 31 families were interviewed in both countries, across a diverse range of socioeconomic and cultural groups. Practical issues like access, worktime, and forgetfulness are prevalent among lower-income non-white families in both countries. On the contrary, informed decisions not to vaccinate linked to neoliberal parenting values are found among higher-income white families. In affluent hesitant families, individuality, freedom, and parental autonomy guide decisions. Each child is viewed uniquely, with vaccination decisions shaped by context, marked by racial and social class distinctions. Criticism of the medical-pharmaceutical industry, profit prioritization over health, and preference for alternative medicines drive distrust, portraying those families as 'anti-system' rather than anti-vaccine. South Africa's lower-income black families also adopt an anti-system stance: to them the ‘system’ is any intervention seen as ‘western’, including vaccination. These findings reiterate that historical, cultural, and social backgrounds inform health decision-making processes. We highlight how socioeconomic and racial/ethnic inequalities stand out in interviewees’ narratives, whether in the perception of protection due to belonging to a socially privileged group or in the belief of not belonging to the hegemonic health system.