Alternative beliefs about HIV – such as the man-made origins of the virus or the existence of a cure – can undermine trust in and engagement with HIV prevention and treatment initiatives. It is therefore crucial to study the reasons why these beliefs are plausible to some individuals, and how we might better address them in future prevention and treatment campaigns. This study contributes to understanding these beliefs by examining the explanations provided by African respondents in Khayelitsha Township for the plausibility of alternative beliefs about HIV and AIDS. Drawn from a sub-selection of over 2900 respondents to the Cape Area Panel Study, ten focus group discussions (n=47) were held with African men and women from the township of Khayelitsha. Previous studies maintain that the experience of apartheid, of former President Mbeki’s AIDS denialism, and of the unsettling transformations of globalisation have negatively influenced the South African public’s trust in biomedical claims. This paper argues that in addition to these explanations, individuals express distrust about HIV science because certain aspects of these scientific explanations do not ‘add-up’, particularly when considered in light of their everyday observations and experiences. These disjunctures in information do not simply reflect a lack of HIV knowledge or rejection of scientific principles. Rather, in drawing on past and present experiences, individuals demonstrate their commitment to “street-level epistemologies of trust”, an informal manner of empirically engaging with science’s rationale. HIV prevention campaigns should draw on experiential aspects of HIV and AIDS to lend credibility to scientific claims and recognize that some doubts about science are a form of skeptical engagement rather than an outright rejection.