BACKGROUND: There have been resurgent efforts in Africa to estimate the public health impact of malaria control interventions such as insecticide treated nets (ITNs) following substantial investments in scaling-up coverage in the last five years. Little is known, however, on the effectiveness of ITN in areas of Africa that support low transmission. This hinders the accurate estimation of impact of ITN use on disease burden and its cost-effectiveness in low transmission settings. METHODS AND PRINCIPAL FINDINGS: Using a stratified two-stage cluster sample design, four cross-sectional studies were undertaken between March-June 2007 across three livelihood groups in an area of low intensity malaria transmission in South Central Somalia. Information on bed net use; age; and sex of all participants were recorded. A finger prick blood sample was taken from participants to examine for parasitaemia. Mantel-Haenzel methods were used to measure the effect of net use on parasitaemia adjusting for livelihood; age; and sex. A total of 10,587 individuals of all ages were seen of which 10,359 provided full information. Overall net use and parasite prevalence were 12.4% and 15.7% respectively. Age-specific protective effectiveness (PE) of bed net ranged from 39% among <5 years to 72% among 5-14 years old. Overall PE of bed nets was 54% (95% confidence interval 44%-63%) after adjusting for livelihood; sex; and age. CONCLUSIONS AND SIGNIFICANCE: Bed nets confer high protection against parasite infection in South Central Somalia. In such areas where baseline transmission is low, however, the absolute reductions in parasitaemia due to wide-scale net use will be relatively small raising questions on the cost-effectiveness of covering millions of people living in such settings in Africa with nets. Further understanding of the progress of disease upon infection against the cost of averting its consequent burden in low transmission areas of Africa is therefore required.