The occurrence of cross-resistance among melarsoprol-resistant Trypanosoma brucei rhodesiense isolates was investigated in this study. The isolates, T. b. rhodesiense KETRI 237, 2538, 1992, 2709, 2694 and 3530, had been obtained from sleeping sickness patients in Kenya and Uganda between 1960 and 1985. Five groups consisting of six mice each were inoculated intraperitoneally with 10(5) parasites of each isolate, and 24 h later treated with either melarsoprol, homidium chloride, diminazene aceturate or isometamidium chloride. The control group comprised infected but untreated mice. The mice were monitored for cure for a period of 60 days post-treatment. The mean prepatent period in the control mice was 5 days while the mean survival period was 22 days. Five of the stabilates, KETRI 237, 2538, 2709, 2694, and 3530, were confirmed to be melarsoprol resistant. Cross-resistance was observed, with the majority of the isolates being resistant to homidium chloride (5/6) and diminazene aceturate (5/6), but all were sensitive to isometamidium chloride (6/6). However T. b. rhodesiense KETRI 1992, which was previously considered as melarsoprol resistant, was sensitive to all the drugs tested. In conclusion, our study has revealed the existence of cross-resistance among the melarsoprol resistant isolates which could only be cured by isometamidium.