The failure rate of melarsoprol after treatment of late stage cases of Human African Trypanosomiasis (HAT) is usually under 7%, even though the drug has been used for such treatment over the past 50 years. We report a melarsoprol treatment failure rate of 26.9% among 428 patients treated in Northern Uganda. Whatever its origin, this observation, the first documented in a HAT focus, is alarming, particularly since no second line trypanocidal drug is actually available for the treatment of late stage HAT. We believe that the current worrisome situation of HAT in several African countries and the risk of emergence of other foci of resistance, argue in favour of a greater attention on the part of the scientific community and the pharmaceutical companies being paid to this problem.