Quinine is a standard drug for treating severe malaria in Africa, and it is also increasingly used to treat uncomplicated disease. However, failures of quinine therapy are common, and it is unknown if failures in Africa are due to drug resistance. Recent studies have identified associations between in vitro quinine sensitivity and polymorphisms in genes encoding putative transporters, including well-described polymorphisms in pfcrt and pfmdr1 and varied numbers of DNNND or DDNHNDNHNND repeats in microsatellite 4760 (ms4760) of the predicted sodium-hydrogen exchanger, pfnhe1. To better characterize mediators of quinine response, we assessed associations between genetic polymorphisms, in vitro quinine sensitivity, and quinine treatment responses in Kampala, Uganda. Among 172 fresh clinical isolates tested in vitro, decreasing sensitivity to quinine was associated with accumulation of pfmdr1 mutations at codons 86, 184, and 1246. Nearly all parasites had pfcrt 76T, preventing analysis of associations with this mutation. pfnhe1 ms4760 was highly polymorphic. Parasites with 2 copies of either ms4760 repeat showed modest decreases in quinine sensitivity compared to those with 1 or ≥3 repeats, but the differences were not statistically significant. None of the above polymorphisms predicted treatment failure among 66 subjects treated with quinine for uncomplicated malaria. Our data suggest that quinine sensitivity is a complex trait and that known polymorphisms in pfcrt, pfmdr1, and pfnhe1, while associated with quinine sensitivity, are not robust markers for quinine resistance.