The HIV-1 has evolved swiftly and the scenario of HIV-1 genetic diversity is constantly changing. In South America, recombinant forms of subtypes B, F1, and BF1 have historically driven the HIV-1 epidemic. In recent years, however, infection with subtype C has gained prominence as its prevalence increased in Southern Brazil as well as neighboring countries. Current studies point to a single introduction of closely related strains as the beginning of the Brazilian subtype C epidemic. However, the place of origin of these strains, date, and route of introduction are under continuous debate as well as the clinical outcomes of the emergence of subtype C. Therefore, this paper reviews the history of the HIV-1 subtype C in Brazil, particularly in the Southern region, covering its demographic and evolutionary history and the possible implications to the Brazilian AIDS epidemic as well as to neighboring countries.