A mouse model of Trypanosoma brucei rhodesiense that can be used in pathogenesis and drug studies for Human African Trypanosomosis (HAT) has so far not been developed. In an attempt to develop such a model, a study was undertaken to determine the clinical and pathological changes in mice infected with stock of T. b. rhodesiense (KETRI 2357) and its clone (KETRI 3741). The infections resulted in a mean prepatent period of 3 (range 3-4) days for KETRI 2537 and 4 (range 3-5) days for KETRI 3741. The first wave of parasitaemia for both isolates reached peak (antilog 8.7) between 6-8 DPI and was followed by secondary latency. Thereafter, the parasitaemia increased and remained high, with slight fluctuations. The mean survival period was 36 (range: 7-45) and 50 (18-82) days for the mice infected with KETRI 2537 and KETRI 3741 respectively. At post mortem, the spleens were enlarged and there was generalized congestion in most organs. Histopathological changes were more severe in the parent stock compared to its clone. Meningoencephalitis was observed in mice infected with KETRI 3741 that survived up to 77 days. These studies demonstrate the development of late stage disease in mice infected with T. b. rhodesiense, with potential for use as a model of sleeping sickness.