Infection with HIV-1 results in the progressive dysfunction of the immune system eventually leading to AIDS, characterised by low CD4+ T lymphocyte counts and increased susceptibility to opportunistic infections. In contrast to HIV-1, individuals infected with HIV-2 often remain asymptomatic, with lower viral loads and higher CD4+ T cell counts throughout the course of disease. Furthermore, HIV-2+ individuals display enhanced HIV-specific T cell responses. In addition, HIV-1 disease progression is slower in patients with pre-existing HIV-2 infection. Plasmacytoid dendritic cells (pDCs) are key mediators of the early innate immune response. Upon viral infection, pDCs secrete high levels of type I IFN (IFN-α/β) which limit viral replication and prime the adaptive immune response. Activated pDCs, in particular excessive IFN-α/β, have been implicated in HIV-1 immunopathogenesis. Specifically pDCs may contribute to the recruitment of target cells to the site of HIV-1 infection, increased apoptosis of immune cells and suppression of memory T cell responses. The aim of this study was to compare the abilities of HIV-1 and HIV-2 to activate pDCs in vitro. HIV-1 was a more potent inducer of type I IFN responses in PBMCs compared to HIV-2, measured at both the transcriptional level, and by measuring IFN-α/β secretion into cell culture supernatants. Furthermore, HIV-2, but not HIV-1, inhibited IFN-α production in response to synthetic stimuli. Phenotypic analysis of pDCs by flow cytometry revealed that both HIV-1 and HIV-2 were equally able to induce an up-regulation of co-stimulatory marker expression. Measurement of co-stimulatory molecule expression in conjunction with IFN-α secretion showed that HIV-1 favoured an IFN response, whereas HIV-2 preferentially maturated pDCs towards an antigen-presenting cell (APC) phenotype. The ability of HIV-2 to mature pDCs into APCs while reducing IFN-α secretion may be an important contributor to more robust T cell responses and therefore slower progressing HIV disease.