BACKGROUND: Mosquito vectors of malaria in Southeast Asia readily feed outdoors making malaria control through indoor insecticides such as long-lasting insecticidal nets (LLINs) and indoor residual spraying more difficult. Topical insect repellents may be able to protect users from outdoor biting, thereby providing additional protection above the current best practice of LLINs. METHODS AND FINDINGS: A double blind, household randomised, placebo-controlled trial of insect repellent to reduce malaria was carried out in southern Lao PDR to determine whether the use of repellent and long-lasting insecticidal nets (LLINs) could reduce malaria more than LLINs alone. A total of 1,597 households, including 7,979 participants, were recruited in June 2009 and April 2010. Equal group allocation, stratified by village, was used to randomise 795 households to a 15% DEET lotion and the remainder were given a placebo lotion. Participants, field staff and data analysts were blinded to the group assignment until data analysis had been completed. All households received new LLINs. Participants were asked to apply their lotion to exposed skin every evening and sleep under the LLINs each night. Plasmodium falciparum and P. vivax cases were actively identified by monthly rapid diagnostic tests. Intention to treat analysis found no effect from the use of repellent on malaria incidence (hazard ratio: 1.00, 95% CI: 0.99-1.01, p = 0.868). A higher socio-economic score was found to significantly decrease malaria risk (hazard ratio: 0.72, 95% CI: 0.58-0.90, p = 0.004). Women were also found to have a reduced risk of infection (hazard ratio: 0.59, 95% CI: 0.37-0.92, p = 0.020). According to protocol analysis which excluded participants using the lotions less than 90% of the time found similar results with no effect from the use of repellent. CONCLUSIONS: This randomised controlled trial suggests that topical repellents are not a suitable intervention in addition to LLINs against malaria amongst agricultural populations in southern Lao PDR. These results are also likely to be applicable to much of the Greater Mekong Sub-region. TRIAL REGISTRATION: This trial is registered with number NCT00938379.