A nationwide yearly cycle of indoor residual spraying (IRS) with a pyrethroid, alphacypermethrin, at a dosage of 50 mg/m(2) was instituted in 2004 in the Democratic Republic of São Tomé and Príncipe. Rates of IRS acceptance were high, varying from 82% to 95% for dwellings and outhouses. Epidemiologic surveys of the children < 9 years of age before and after the first IRS cycle revealed a rapid reduction in malaria. Overall prevalence of malaria parasitemia for all districts was lowered from 20.1% to 2.8% at 12 months after the first IRS and reached 0.7% at 8 months after the second IRS. Longer insecticidal persistence was found on wood than on cement with alphacypermethrin.