Human immunodeficiency virus type 2 (HIV-2), originally restricted to Western Africa, is now spreading to Western European countries because of migration from endemic areas. Therefore, it is mandatory to enforce the surveillance and improve the diagnostics of this neglected infection. In this report, we describe a case of HIV-2 infection affecting an Italian citizen along with three cases from India. Phylogenetic analysis showed that the viral strain identified in the Italian patient clustered with a strain isolated from an immigrant living in France. Of the three Indian strains, two clustered together and were statistically supported, whereas one clustered with a strain from Guinea Bissau. The description of the first case of HIV-2 infection in an Italian citizen indicates that the virus is spreading from endemic areas to countries involved in migration. A strict monitoring and improvement of the diagnostic molecular tools are necessary to avoid misdiagnosis with relevant clinical consequences.