Many people remain at risk of becoming HIV-infected despite large-scale prevention efforts. An exploratory study was conducted to investigate the determinants of a fatalistic attitude towards protecting the self from HIV/AIDS. The study utilised the Human Sciences Research Council’s national, representative EPOP-survey among South African adults age 18 and over (n = 2 494). Frequencies were calculated for all the items, and scales were compiled for perceived hopelessness, self-efficacy to effect change and future goals. Chi-square analysis was conducted between indicators of fatalism and demographic variables. A sequential logistic regression analysis was applied to the variables: feelings of hopelessness, self-efficacy, future goals and socio-demographics, as possible determinants of a fatalistic view about protecting one’s self from HIV/AIDS. About 30% of the South African adult population aged 18 and over indicated such a fatalistic view. The results of logistic regression indicated that participants who reported a low level of self-efficacy to effect change, a low living standard, feelings of hopelessness, and unclear future goals were more likely to express a fatalistic attitude towards HIV/AIDS protection than others. A better balance is required between a focus on individual risk factors and an understanding of the processes through which individuals are affected by socio-economic, cultural and political contexts. On the individual level, general resources for living need to be developed, while the altering of contexts and structures in which communities function is crucial. A person-centred development framework in support of health and well-being could augur well for HIV prevention.