Adult Microtus montanus were inoculated with a recently isolated strain of Trypanosoma brucei rhodesiense of human origin. The animals developed subacute to chronic infection and low-grade parasitemia. Histopathological examination of the heart revealed a severe pancarditis resulting in pronounced weight loss, and survival times of 5–8 weeks, preventing development of meningoencephalitis. In the brain a moderate meningitis was found, usually associated with moderate numbers of parasites in the choroid plexus and leptomeninges; however, trypanosomes were also found without tissue inflammation. Meningoencephalitis was found after 7 weeks, with parasites in the cerebral parenchyma. Chronic inflammation was present in lungs and kidney, often associated with trypanosomes; in one animal glomerulonephritis was found. Spleen and lymph glands showed a variable degree of lymphoid hyperplasia but no extravascular parasites. In the liver of all animals plasmolymphoid infiltrates were observed in the periportal connective tissue; no extravascular parasites were observed. A variable degree of lymphoplasmohistiocytic infiltrate in the connective tissue and occasional rare trypanosomes were seen in mesenterium, pancreas, epididymis, striated muscle, and skin. Experimental infection in M. montanus appears to be a suitable model for study of the acute trypanosomiasis of T. b. rhodesiense, but not for chronic African sleeping sickness with cerebral involvement.