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HIV/AIDS epidemics affect the functioning of society in several ways. The inability of the extant literature to adequately highlight cultural factors and practices that favour and/or mitigate the spread of the disease necessitated the study. The study examined how socio-cultural factors engender vulnerability to HIV epidemic in Enugu South Local Government Area of Enugu State, Nigeria. Health Belief Model was used as analytical framework in explaining explains why belief, vulnerability and attitudes of people affect disease spread. The study adopted two-prong methodological approach – qualitative and quantitative research technique: primary data was gathered using structured questionnaire while secondary data was gathered from relevant and related literature. The sample size of this research study was 200 respondents, method of selection was multi-stage cutting across sex, age, income level, faith/religion, etc. The method of analysis was principal component analysis (factor analysis). The major findings from the study showed that blood covenants/oaths, tribal marks, having multiple female partners, and polygamy were key factors engendering vulnerability to HIV epidemic in Enugu South Local Government Area. The study further recommended awareness campaign with socio-cultural sensitive messages geared towards bringing HIV/AIDS under control in Enugu South Local Government Area of Enugu State, Nigeria.