Greece has experienced early the effect of HIV/AIDS on morbidity and mortality. The era of highly active antiretroviral therapy has alleviated many of the consequences of the epidemic, however, HIV infection remains an issue of utmost significance. Men who have sex with men are the driving force of the HIV epidemic in Greece followed by heterosexually-infected individuals, while infections among injecting drug users remain at low levels. HIV-1 molecular epidemiology studies reveal a high genetic heterogeneity amongst the circulating strains in Greece. The epidemic began with subtype B, as in most of the European countries, however, subtype A was detected at a high prevalence among the newly diagnosed HIV-1-infected individuals in recent years. HIV requires an effective and sustained response meeting the needs of vulnerable subpopulations.