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To investigate why Southern sub-Saharan Africa is more severely impacted by HIV and AIDS than other parts of sub-Saharan Africa, I conducted a review of the literature that assessed viral, host and transmission (societal) factors. This narrative review evaluates: 1) viral factors, in particular the aggregation of subtype-C HIV infections in Southern sub-Saharan Africa; 2) host factors, including unique behaviour patterns, concomitant high prevalence of sexually transmitted diseases, circumcision patterns, average age at first marriage and immunogenetic determinants; and, 3) transmission and societal factors, including levels of poverty, degrees of literacy, migrations of people, extent of political corruption, and the usage of contaminated injecting needles in community settings. HIV prevalence data and published indices on wealth, fertility, and governmental corruption were correlated using statistical software. The high prevalence of HIV in Southern sub-Saharan Africa is not explained by the unusual prevalence of subtype-C HIV infection. Many host factors contribute to HIV prevalence, including frequency of genital ulcerating sexually transmitted infections, absence of circumcision (compiled odds ratios suggest a protective effect of between 40% and 60% from circumcision), and immunogenetic loci, but no factor alone explains the high prevalence of HIV in the region. Among transmission and societal factors, the wealthiest, most literate and most educated, but also the most income-disparate, nations of sub-Saharan Africa show the highest HIV prevalence. HIV prevalence is also highest within societies experiencing significant migration and conflict as well as in those with government systems experiencing a high degree of corruption. The interactions between poverty and HIV transmission are complex. Epidemiologic studies currently do not suggest a strong role for the community usage of contaminated injecting needles. Areas meriting additional study include clade type, host immunogenetic determinants, the complex interrelationship of HIV with poverty, and the community usage of contaminated injecting needles.