Resolution of infection by Leishmania sp. is critically dependent on activation of CD4(+) T helper cells. Naive CD4(+) T helper cells are primed by dendritic cells which have responded to an activation signal in the periphery. However, the role of Leishmania-infected dendritic cells in the activation of an anti-Leishmania immune response has not been comprehensively addressed. Using the highly controlled model system of bone marrow-derived dendritic cell infection by Leishmania mexicana cultured in vitro, we show that uptake of L. mexicana parasites does not result in activation of immature dendritic cells or secretion of IL-12. Incubation with L. mexicana promastigotes results in the activation of a small percentage of dendritic cells which do not appear to contain whole parasites. Activation of dendritic cells is not suppressed by infection, since infected cells can be fully activated on addition of activating stimuli. Therefore, uptake of intact Leishmania mexicana parasites is not sufficient to activate dendritic cells in vitro. We propose that these data provide a basis for interpreting the interactions between dendritic cells and all Leishmania sp.