Treatment efficacy is related to the interaction of three parameters: drug, parasites, and human factors. The role of human factors in treatment outcome has been poorly documented to date, although human genetic factors and specific immunity have been related to protection against malaria. This study aimed to evaluate a possible cooperation between drug efficacy and host factors in treatment success. The contribution of host factors to treatment efficacy was studied in Gabonese children with a non-severe malaria attack. Children (n=232) aged under 10 years were treated with either sulfadoxine-pyrimethamine or amodiaquine. The influence of erythrocyte-related genetic factors and humoral immune responses (IgG and subclasses) against MSP1(19) on anti-malarial treatment outcome during a 28-day follow-up was studied. Sickle-cell trait carriage and anti-MSP1(19) IgG3 levels were related to lower parasite densities at enrolment (multiple linear regression analysis, P<or=0.005). Strikingly, early failures after AQ or SP treatment were associated with decreased anti-MSP1(19) IgG, IgG1 and IgG3 levels at enrolment. However, this finding was achieved in a low number of children presenting with an early failure. Kinetics of anti-MSP1(19) IgG and subclasses between Days 0 and 28 were also related to treatment efficacy, as the most effective treatment (sulfadoxine-pyrimethamine) was characterised by a higher elevation of antibody titres by Day 28. No effect of erythrocyte-related genetic factors on treatment outcome was shown, although the protective role of sickle-cell trait against higher parasitaemias was confirmed at enrolment. Our data suggest that anti-MSP1(19) IgG1 may have a supportive role during the first days of treatment to prevent early failures. The interference between drug efficacy, immunity and human genetic factors needs further investigation to be elucidated.