Trypanosoma brucei gambiense, a causative agent of sleeping sickness, induced a dose-dependent production of tumor necrosis factor (TNF)-alpha by human macrophages in vitro. TNF-alpha was also induced in the Mono Mac 6 cell line, which indicates a direct effect of parasite components on macrophages. Parasite-soluble factors were also potent inducers of TNF-alpha. The addition of anti-TNF-alpha to cocultures of macrophages and parasites increased the number of trypanosomes and their life span, whereas irrelevant antibodies had no effect. TNF-alpha may have a direct role (i.e., direct trypanolytic activity) and/or an indirect one, such as TNF-alpha-mediated induction of cytotoxic molecules. A direct dose-dependent lytic effect of TNF-alpha on purified parasites was observed. This lytic effect was inhibited by anti-TNF-alpha. These data suggest that, as in experimental trypanosomiasis, TNF-alpha is involved in parasite growth control in human African trypanosomiasis.