The disposition of chlorproguanil/dapsone (one daily dose for 3 d of 1.2 and 2.4 mg/kg respectively) has been studied in young children with Plasmodium falciparum malaria, to provide data complementary to a clinical trial of this drug combination. Unbound concentrations of chlorcycloguanil (the active metabolite of chlorproguanil) and dapsone in clinical samples have been related to the unbound drug concentrations which produced defined outcomes in tests in vitro of drug efficacy and toxicity. Twelve children with uncomplicated malaria were treated: all cleared parasitaemia within 72 h and made uneventful recoveries. After the first dose of chlorproguanil/dapsone the maximum unbound chlorcycloguanil concentration in clinical samples (19 ng/mL [about 60 nM]) was 2 orders of magnitude above the 50% inhibitory concentration (IC50) value for this drug against the K39 stain of P. falciparum, while falling 2 orders of magnitude below its IC50 against human bone marrow cells; the maximum unbound dapsone concentration in clinical samples (160 ng/mL [about 645 nM]) was 10-fold higher than its IC50 against the K39 strain. However, because of the rapid elimination of chlorproguanil from the body (half-life 12.6 +/- 6.3 h), the minimum fractional inhibitory concentrations of unbound chlorcycloguanil/dapsone against the K39 strain were probably exceeded for no more than 6 d. These data, together with the clinical trial, will be helpful in deciding whether current chlorproguanil/dapsone doses are optimal for the treatment of falciparum malaria.