Co-stimulatory signals are necessary for the full activation of T cells for growth and effector function. As co-stimulatory molecules are normally regulated in their expression, it has been suggested that microorganisms enhance their expression on host antigen-presenting cells (APC), thus allowing efficient generation of anti-microbial immunity. We here describe experiments which demonstrate that infection of macrophages, both in vitro and in vivo, by the protozoan parasite Leishmania donovani fails to trigger expression of co-stimulatory molecules B7-1 and heat-stable antigen on these APC. Furthermore, infection with this parasite inhibits the macrophage response to normal regulatory signals, such as bacterial lipopolysaccharide. These changes in the cell surface are mirrored in functional studies of co-stimulation in vitro. Together, these data suggest a further facet of parasite interference in host immunity, but also indicate a potential new target for immunotherapy.