BACKGROUND: Positive Choices is a whole-school social marketing intervention to promote sexual health among secondary school students. Intervention comprises school health promotion council involving staff and students coordinating delivery; student survey to inform local tailoring; teacher-delivered classroom curriculum; student-run campaigns; parent information; and review of sexual/reproductive health services to inform improvements. This trial builds on an optimisation/pilot RCT study which met progression criteria, plus findings from another pilot RCT of the Project Respect school-based intervention to prevent dating and relationship violence which concluded such work should be integrated within Positive Choices. Young people carry a disproportionate burden of adverse sexual health; most do not report competence at first sex. Relationships and sex education in schools can contribute to promoting sexual health but effects are small, inconsistent and not sustained. Such work needs to be supplemented by 'whole-school' (e.g. student campaigns, sexual health services) and 'social marketing' (harnessing commercial marketing to social ends) approaches for which there is good review-level evidence but not from the UK. METHODS: We will conduct a cluster RCT across 50 schools (minimum 6440, maximum 8500 students) allocated 1:1 to intervention/control assessing outcomes at 33 months. Our primary outcome is non-competent first sex. Secondary outcomes are non-competent last sex, age at sexual debut, non-use of contraception at first and last sex among those reporting heterosexual intercourse, number of sexual partners, dating and relationship violence, sexually transmitted infections, and pregnancy and unintended pregnancy for girls and initiation of pregnancy for boys. We will recruit 50 school and undertake baseline surveys by March 2022; implement the intervention over the 2022-2024 school years and conduct the economic and process evaluations by July 2024; undertake follow-up surveys by December 2024; complete analyses, all patient and policy involvement and draft the study report by March 2025; and engage in knowledge exchange from December 2024. DISCUSSION: This trial is one of a growing number focused on whole-school approaches to public health in schools. The key scientific output will be evidence about the effectiveness, costs and potential scalability and transferability of Positive Choices. TRIAL REGISTRATION: ISRCTN No: ISRCTN16723909 . Trial registration summary: Date:. Funded by: National Institute for Health Research Public Health Research Programme (NIHR131487). SPONSOR: LSHTM. Public/scientific contact: Chris Bonell. Public title: Positive Choices trial. Scientific title: Phase-III RCT of Positive Choices: a whole-school social marketing intervention to promote sexual health and reduce health inequalities. Countries of recruitment: UK. INTERVENTION: Positive Choices. INCLUSION CRITERIA: Students in year 8 (age 12-13 years) at baseline deemed competent by schools to participate in secondary schools excluding pupil referral units, schools for those with special educational needs and disabilities, and schools with 'inadequate' Ofsted inspections. STUDY TYPE: interventional study with superiority phase III cluster RCT design. Enrollment: 1/9/21-31/3/22. SAMPLE SIZE: 50 schools and 6440-8500 students. Recruitment status: pending. PRIMARY OUTCOME: binary measure of non-competent first sex. SECONDARY OUTCOMES: non-competent last sex; age at sexual debut; non-use of contraception at first and last sex; number of sexual partners; dating and relationship violence (DRV) victimisation; sexually transmitted infections; pregnancy and unintended pregnancy for girls and initiation of pregnancy for boys using adapted versions of the RIPPLE measures. Ethics review: LSHTM research ethics committee (reference 26411). Completion data: 1/3/25. Sharing statement: Data will be made available after the main trial analyses have been completed on reasonable request from researchers with ethics approval and a clear protocol. Amendments to the protocol will be communicated to the investigators, sponsor, funder, research ethics committee, trial registration and the journal publishing the protocol. Amendments affecting participants' experience of the intervention or important amendments affecting the overall design and conduct of the trial will be communicated to participants.