Chlorpheniramine (CP), a histamine H1-receptor antagonist, enhances the efficacy of chloroquine (CQ) in acute uncomplicated falciparum malaria. The effects of this combination therapy on the pharmacokinetic disposition of CQ is, however, unpredictable. A standard treatment with 25 mg CQ base per kg bodyweight was orally administered over 3 days, alone or in combination with CP, to 17 semi-immune Nigerian children with Plasmodium falciparum parasitaemia attending hospital in Lagos, Nigeria, and observed for 28 days. Whole-blood CQ concentrations were monitored 14 times during the follow-up by high-performance liquid chromatography analysis of blood dried on filter paper. Parasitaemia was determined on thick blood films stained with Giemsa, and treatment failures were established following the WHO classification for CQ resistance. Our pharmacokinetic data showed that the peak whole-blood CQ concentration was significantly increased (P < 0.05) by CP administration, and the time to achieve the peak was reduced in the presence of CP. The area under the first-moment drug-concentration-time curve was also significantly increased (P < 0.05) by CP administration. Treatment with CQ-CP combination resulted in a shorter parasite clearance time (2.0 +/- 0.5 days) and a higher cure rate (87.5%) compared to treatment with CQ alone (3.5 +/- 0.5 days; 66.7%). Our data suggest that CP enhanced the efficacy of CQ against resistant P. falciparum in acute uncomplicated malaria by increasing the uptake/concentration of CQ in resistant parasites.