IntroductionHeterogeneous coverage threatens to compromise the effectiveness of immunization programs in Zambia. Demand-creation initiatives are needed to address this; however, there is incomplete understanding of why vaccine coverage is suboptimal. We investigated overarching perceptions on vaccine acceptability, hesitancy, and accessibility at three informal settlements in Lusaka, Zambia. MethodsNested within a cholera vaccination uptake study, we sought to understand overarching perceptions on vaccines’ hesitancy in three informal settlements in Lusaka, Zambia. We conducted 48 focus group discussions with a convenience sample of laypersons, lay healthcare workers, neighbourhood health committee members and vaccinators. ResultsBoth laypersons and community-based health actors reported high vaccine acceptance though several sources of hesitancy were reported. Traditional remedies, alcohol use and religious beliefs emerged as drivers of vaccine hesitancy, likely reinforced by a background of distrust towards western medicine. Also mentioned were previous adverse events, fear of injections and low perceived need for immunization. Limited understanding of how vaccines work and overlapping local terms for vaccine and other medical concepts created confusion and inaccurate views and expectations. Some reported refusing injections to avoid pain and perceived risk of infection. Discussants emphasised the importance of education and preferred mobile immunization campaigns, with weekend to reach those with poor access and delivered by a combination of professional and volunteer workers. ConclusionsVaccine hesitancy in Zambia is underpinned by many factors including personal experiences with vaccinations, alternative belief models, limited knowledge, deep misunderstanding about how vaccines work, and barriers to access. To overcome these, community-driven models that incorporate factual communication by professionals and operate outside of traditional hours, may help. Better research to understand community preferences for vaccine uptake could inform interventions to improve immunization coverage in Zambia.