Treatment of malaria has become increasingly difficult due to high levels of resistance to the cheap and commonly used antimalarials. In Guinea-Bissau, the first line drug is chloroquine (CQ), the second line drug is sulfadoxine-pyrimethamine (S/P), and the third line therapy is quinine (QU). During the last ten years we have studied these drugs in the Bandim area at the outskirt of the capital Bissau, to a large extent with the same methodology and the same staff. Chloroquine given in the standard total dose of 25 mg/kg proved to be less efficient with an adequate clinical and parasitological response (ACPR) rate on day 28 of 68% in 1996/1997 and 76% in 2001/2004. A higher total dose of 50 mg given in two daily doses over three days showed an ACPR rate of 86% and 90%. No severe adverse effects were found. Artemisinin derivatives reduce the parasite load and improve thereby in theory the efficacy of the partner drug. However, treatment with artesunate and CQ was no better than with CQ alone. Artesunate monotherapy for three days gave high treatment failure rates of 50% on day 35. S/P was efficient both as first and second line treatment with 35 day cure rates of 86% and 90%, respectively. No decrease in efficacy was seen from 1996 till 2004. However, as a high rate of mutations associated with resistance to S/P has been found in Guinea-Bissau its use should be restricted in order to prolong its period of usefulness. Quinine has traditionally been used during three days for treatment of uncomplicated malaria in Guinea-Bissau. However, treatment for 3 days gave high treatment failure rates. QU for three days followed by a standard dose of CQ did not add to the cure rate of CQ monotherapy and should therefore be abandoned and replaced by quinine for the full seven days. Amodiaquine (AQ) has been proposed as first line treatment when CQ 25 mg/kg has to be abandoned due to the level of resistance. We compared treatment with AQ and CQ. High rates of ACPR on day 35 were found treating with AQ 15 and 30 mg/kg (88% and ...