Trypanosome-derived lymphocyte-triggering factor (TLTF) produced by Trypanosoma brucei brucei stimulates production of interferon-γ (IFN-γ) by CD8 T cells, and it is reported that, in turn, IFN-γ stimulates proliferation of T. b. brucei. We studied the role of TLTF in trypanosome proliferation using the Wellcome strain (WS) of Trypanosoma brucei gambiense and the ILtat 1.4 strain (IL) of T. b. brucei. Increase in the number of WS in infected rats is more rapid than IL and corresponds with comparatively higher levels of IFN-γ. Production of IFN-γ, as measured by protein and messenger RNA (mRNA) levels, was maintained by splenocytes from WS-infected rats, whereas levels decreased in IL-infected rats, accompanied by prolongation of infection. Expression of TLTF mRNA by in vitro–cultured WS was promoted in a dose-dependent fashion by addition of recombinant rat IFN-γ at all concentrations tested. The addition of lower concentrations of IFN-γ to cultured IL increased expression of TLTF mRNA, whereas, in contrast to WS, addition of 100 and 1,000 U/ml IFN-γ decreased expression of TLTF by IL. These results show that unlike WS, elevated IFN-γ concentrations lead to decreased TLTF production by IL. It is believed that decreased TLTF production in IL-infected rats leads to lowered IFN-γ production, thereby slowing IL proliferation.