BackgroundWide recognition that structural factors are important in the HIV epidemic has not generated much evidence of impact of structural interventions. Few randomised controlled trials of structural interventions for HIV prevention have an HIV endpoint, and most of those did not show a significant impact. It has proved difficult to prevent new HIV infections in Botswana, especially among young women, many of whom are unable to act on HIV preventive choices. Proposed by a government think tank in Botswana, the Inter-ministerial National Structural Intervention trial (INSTRUCT) tests whether addressing social and economic factors, including gender inequality, gender violence, poverty, and poor access to education, can lower HIV infection rates among young women. Focussed on increasing access by marginalised young women to government support programs, the intervention seeks to change their structural position, reducing their vulnerability to transactional sex, and thus to HIV infection.MethodsThis parallel group cluster randomised controlled trial compares HIV rates among young women in districts with and without the structural interventions. The 30 administrative districts in the country, stratified by HIV prevalence and development status, will be randomly assigned to 5-district implementation waves. The intervention in the first-wave districts will include: (i) recruiting and preparing vulnerable young women to apply to government support programs, (ii) making the support programs more accessible to young women by engaging local program officers and young women in co-evaluation of programs and co-design of solutions; and (iii) generating an enabling environment for change in communities through an audio-drama edutainment program. In year five, an impact survey will measure HIV rates among vulnerable young women (15–29 years) in a random sample of communities in the five intervention districts and in the five second-wave (control) districts. Fieldworkers will undertake rapid HIV screening and interview young women and young men, collecting information on secondary outcomes of attitudes and behaviours.DiscussionThis is the first step in a planned stepped-wedge design that will roll out the intervention, modified as necessary, to all districts. Strong government commitment provides an important opportunity to reduce new HIV cases in Botswana, and guide prevention efforts in other countries.Trial registrationRegistration number: ISRCTN 54878784. Registry: ISRCTN. Date of registration: 11 June 2013.