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We have analysed the Trypanosoma brucei gene TbAT1, which codes for the P2 adenosine transporter, to investigate a possible link between the presence of mutations in this gene and trypanocidal drug resistence. About 70% of T .b. gambiense isolates from a focus in North Western Uganda with high treatment failure rates following mclarsoprol therapy had a mutations within TbAT1. Unexpectedly, all individual isolates contained the same set of nine mutations in their TbAT1 genes. Identical sets of mutations were also found in a multi-drug resistant T.b.rhodesiense isolate from South Eastern Uganda and in a T.b.gambiense isolate from a relapsing patient from Northern Angola. Quantitative analysis of isolates from North western Uganda revealed that mclarsoprol relapse patients have significantly more infections with mutant TbATl (c2 = 6.70; d.f = 1; p = 0.0097, two tailed). Genetic knock out of TbAT1 of bloodstream trypanosomes did no affect in vitro cell proliferation, as well as mouse infectivity. However, the cells were rendered up to four times less susceptible to mclarsoprol. mclarsene oxide, and diminazene aceturate. In vivo experiments revealed that mouse infections of TbAT1 knock out clones could not be treated with four injections of 2mg/kg melarsoprol, while the same dose cured all the animals infected with the wild type clone. We conclude that loss of P2 transport activity significantly contributes to the increased drug resistence in African trypanosomes.