Intermittent preventive treatment of malaria in infants (IPTi) with sulphadoxine-pyrimethamine shows evidence of efficacy in individually randomized, controlled trials. In a large-scale effectiveness study, IPTi was introduced in April 2005 by existing health staff through routine contacts in 12 randomly selected divisions out of 24 in 6 districts of rural southern Tanzania. Coverage and effects on malaria and anemia were estimated through a representative survey in 2006 with 600 children aged 2-11 months. Coverage of IPTi was 47-76% depending on the definition. Using an intention to treat analysis, parasitemia prevalence was 31% in intervention and 38% in comparison areas (P = 0.06). In a "per protocol" analysis of children who had recently received IPTi, parasite prevalence was 22%, 19 percentage points lower than comparison children (P = 0.01). IPTi can be implemented on a large scale by existing health service staff, with a measurable population effect on malaria, within 1 year of launch.