Dendritic cells (DCs) are fundamental for the initiation of immune responses and are important players in AIDS immunopathogenesis. Impairment of DC function may result from bystander effects of HIV-1 envelope proteins independently of direct HIV-1 infection. HIV-2 envelope proteins are thought to interact with a broader range of receptors than those of HIV-1, and have been shown to have T cell immunosuppressive properties mediated by monocytes. The effects of HIV-2 envelope on DC differentiation and maturation were investigated. The modulatory properties of the HIV-2 envelope on DC generated from monocytes were assessed using both recombinant proteins (HIV-2(ROD) and HIV-2(ALI)) and whole chemically inactivated virus (aldrithiol-2-treated HIV-2(ROD)). DC phenotype was assessed by flow cytometry and DC function by their ability to stimulate allogeneic T cells and to produce cytokines. We demonstrate that HIV-2 Env had no effects upon DC differentiation and maturation despite its broad receptor usage and ability to modulate monocyte function. It is plausible to speculate that a reduced ability of the HIV-2 Env to impair myeloid DC function could represent a contributory factor to the relatively benign course of HIV-2 disease.