OBJECTIVE: To test the efficacy of a new compound drug (CGP 56697) against acute, uncomplicated falciparum malaria. METHOD: Reappearing parasites were analysed by PCR-RFLP within a randomized controlled trial. 130 patients received chloroquine and 130 patients were treated with CGP 56697. Samples from 96 patients with parasitological failure were tested by PCR-RFLP for MSP2 of Plasmodium falciparum. Seven days after treatment 32 patients of the chloroquine control group with reappearing parasites were tested by PCR and one infection was unequivocally determined as a new infection. After 7 days, in the CGP 56697 group, 6 samples were tested in which one new infection was identified. Similar observations were made one and three weeks later in both groups. RESULTS: Although a high multiplicity of infections on admission was observed, there was no significant correlation between multiplicity and either recrudescence or new infection. Patients in both treatment groups with subsequent recrudescent parasites had higher initial mean parasite densities than patients who cleared. Those of the patients with recrudescent parasites who were treated with CGP 56697 had higher initial parasite densities than those treated with chloroquine. The rate of re-infection increased with time as expected in holoendemic areas and appeared to be higher in chloroquine patients. Generally, CGP 56697 showed a superior clearance rate, successfully cleared higher parasite densities and suppressed new infections over a longer period of time. CONCLUSION: The PCR analysis confirmed that reinfections beyond day 7 are significant in areas highly endemic for malaria and showed the necessity of excluding these when estimating 14 day clearance rates. Provided new infections are excluded, the 28-day clearance rate can also be used to determine the efficacy of antimalarial drugs in highly endemic areas, and adds to our knowledge of drug resistance and dynamics of infections in people living in such areas.