African Health Sciences 2011Background: Resistance to the antimalarial drug sulfadoxine-pyrimethamine (SP) emerged in Plasmodium falciparum from Asia in the 1960s and subsequently spread to Africa. In Tanzania, SP use as a national policy began in 1983 as a second line to chloroquine (CQ) for the treatment of uncomplicated malaria, until August 2001 when it was approved to replace CQ as a national first line. Objective: The present study assesses the frequency of resistant dhfr and dhps alleles in Morogoro-Mvomero district in south eastern Tanzania and contrast their rate of change during 17 years of SP second line use against five years of SP first line use. Methodology: Cross sectional surveys of asymptomatic infections were carried out at the end of rainy season during July- September of 2000, when SP was the national second line (CQ was the first line) and 2006 when SP was the national first line antimalarial treatment. Genetic analysis of SP resistance genes was carried out on 1,044 asymptomatic infections and the effect of the two policies on SP evolution compared. Results: The frequency of the most resistant allele, the double dhps-triple dhfr mutant genotype, increased by only 1% during 17 years of SP second line use, but there was a dramatic increase by 45% during five years of SP first line use. Conclusion: We conclude that National policy change from second line to first line SP, brought about an immediate shift in treatment practice and this in turn had a highly significant impact on drug pressure. The use of SP in specific programs only such as intermittent preventive treatment of infants (IPTi) and intermittent preventive treatment of pregnant women (IPTp) will most likely reduce substantially SP selection pressure and the SP resistance alleles alike.