The effect of immunosuppression on the development of drug resistance by trypanosomes was investigated in mice infected with Trypanosoma evansi. As a result of frequent passage in immunosuppressed mice given subcurative drug treatments clones of T. evansi rapidly developed high levels of resistance to mel Cy, diminazene aceturate and isometamidium chloride. Similar protocols in normal immunocompetent mice infected with the same parent clones did not lead to the development of drug-resistance. The resistant populations developed in immunosuppressed mice maintained their high levels of resistance when tested in normal mice. The mel Cy resistant clone was tested for cross-resistance to other trypanocides and was found to be also highly resistant to diminazene and pentamidine. The results indicate that impairment of the host immune system may lead to the rapid development of drug-resistance by T. evansi under experimental conditions in mice and may possibly play a role in the development of drug resistance by trypanosomes in the field.