The hemoflagellate Trypanosoma brucei (T. b.) is the cause of African sleeping sickness. T. b. brucei which is pathogenic for rodents but nonpathogenic for humans was used to examine the interactions between the parasite and mononuclear cells (MNC). Co‐cultivation in vitro of rat or human MNC and T. b. brucei resulted in a rapid non‐antigen‐specific release of interferon‐γ (IFN‐γ) which was dependent on CD8⁺ lymphoid cells. The parasites triggered MNC proliferation if IFN‐γ was blocked by a specific antibody in vitro. Separate cultures of parasites and MNC in a two‐chamber system allowing exchange of soluble mediators showed CD8⁺ cell‐dependent MNC triggering, indicating that a diffusable factor released by trypanosomes acts on the MNC. Gel filtration according to molecular mass of disrupted parasites and assay of the fractions revealed a peak activity at an approximate molecular mass of 185 kDa for the trypanosome‐derived lymphocyte‐triggering factor (TLTF). Conversely, there was a CD8⁺ cell‐dependent action of MNC on the trypanosomes. MNC released a diffusable factor that in short‐term experiments caused a striking increase in number of parasites. This effect was inhibited by antibodies against rat IFN‐γ. The increase in number of trypanosomes was promoted by rat MNC or rat IFN‐γ but not human MNC or human IFN‐γ suggesting a species‐restricted recognition of IFN‐γ. An in vivo uptake of IFN‐γ by the parasites was suggested by immunohistochemical staining of T. b. brucei with an mAb against rat IFN‐γ and Western blot of the parasites showing a band with a molecular mass corresponding to IFN‐γ. The bidirectional signals we define here may explain certain features of trypanosomiasis, i.e. T cell activation, immunosuppression and host‐range restriction. The seemingly important role of the TLTF indicates that it should be purified and explored as target for immune‐specific intervention.