BACKGROUND: Chloroquine (CQ) and Sulfadoxine-Pyrimethamine (SP) are the predominantly used antimalarials in Zambia and other parts of East Africa, but increasing resistance of P. falciparum is a major concern. METHODS: Seventy consecutive patients with uncomplicated falciparum malaria were enrolled. In 43 patients, no prior CQ use could be demonstrated by history and urianalysis (qualitative test, Dill & Glazko) and these patients were given CQ; the other 27 had taken CQ before and received SP. RESULTS: Combined R-II and R-III CQ-resistance was 58% (60% in under-fives), which is the range previously reported from Zambia. By contrast, SP-resistance (R-II and R-III) was much higher (26%) than previously reported (3% - 17%). The history of prior CQ intake correlated well with the results of the Dill-Glazko test; there was no evidence for prior SP intake to explain these results. CONCLUSION: If our findings of SP resistance are confirmed, other drugs such as quinine, atovaquone/proguanil and artemisinin are required to treat malaria in Zambia.