The efficacy of sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) was assessed at Kivunge and Micheweni in Zanzibar, Tanzania, in 2001. The main objective was to obtain baseline data after observations of high levels of chloroquine treatment failures. Children (6-59 months) were randomized to receive either drug. At Kivunge, SP and AQ were given to 64 and 63 cases, while for Micheweni, 61 and 70 cases were treated. Main findings were overall high rates (> 90%) of adequate clinical response (ACR) with AQ. A lower ACR was seen in the SP group at Kivunge (87.1%) compared with Micheweni (94.8%). Furthermore, in the ACR group, 16.7% AQ parasitological resistance (RI-RIII) was encountered at Kivunge. Most of the cases of SP parasitological resistance (14.5%; RI/RII) were seen at Micheweni. Notwithstanding this, the overall treatment failure was only 9.2% with SP and 5.5% with AQ. The Zanzibar Ministry of Health has since reviewed its antimalarial drug policy.