African trypanosomes cause a fatal disease of man and animals that ischaracterized by extensive functional, histological, and pathologicalchanges in the lymphoid tissues of infected hosts, including anincrease in the numbers and activation state of macrophages. Macrophageactivation during infection is the result of exposure of these cells toparasite components and host-derived IFN-γ, produced in response toparasite antigens. The balance of these different activation signalsmay determine the outcome of infection. In the experiments describedhere, we assessed the ability of the variant surface glycoprotein (VSG)of the organism Trypanosoma brucei rhodesiense (T.b.rhodesiense) to activate macrophages directly. Our resultsdemonstrate that macrophages bind and are activated by the VSGmolecule. The resulting profile of activation differs from thatstimulated by IFN-γ. These results suggest that the interaction ofhost macrophages with VSG released during parasite infection may be akey component of trypanosomiasis.