HIV-2 infection was documented for the first time in Venezuela, in a heterosexual couple. Two identical subtype A viral strains exhibiting multiple resistance mutations to antiretroviral drugs were identified. One of the patients suffered from progressive non-immune thrombocytopenia and extranodal NK/T-cell type lymphoma, an association not previously described for HIV-2. His hematological condition promptly improved after onset of an effective antiretroviral therapy.