The response of rabbits, infected with Trypanosoma evansi, to challenge with homologous and heterologous trypanosome species was investigated. Protection against homologous challenge was complete with partial protection obsserved against heterologous T. evansi and Trypanosoma brucei challenge. No protection was seen against challenges with Trypanosoma virax or Trypanosoma Congo Republiclense. The recognition of the surface components of the parasite by the host antibodies was closely linked with complete protection. However, the degree of antigenic relatedness between infection and challenge parasite populations and the magnitude of antibody response to several non-surface components of the parasites appeared to influence the outcome of the challenge infections. Non-antibody dependent factors also appeared to influence the host response to the challenge.