Background <p>Adjuvant endocrine therapy (AET) reduces breast cancer recurrence and mortality. However, up to three quarters of women with breast cancer do not take AET as prescribed. Existing interventions to support adherence have shown limited effectiveness and often do not target the range of barriers to appropriate AET use. We developed four intervention components targeting barriers to AET adherence: Short Message Service (SMS) messages targeting forgetfulness, an information leaflet targeting medication beliefs, a self-management website targeting side-effects, and an acceptance and commitment therapy-based guided self-help programme targeting psychological flexibility. In the preparation phase of the Multiphase Optimisation Strategy (MOST), we conducted an external pilot optimisation trial. We met predefined progression criteria regarding consent, component adherence and availability of outcome measures, and concluded progression to an optimisation randomised controlled trial (O-RCT) was warranted. Our primary aim is to optimise the intervention package to support adherence to AET in women with early-stage breast cancer.</p> Methods <p>We will conduct a multi-centre, individually randomised superiority O-RCT using a 2⁴ factorial design, with nested mixed-methods process and economic evaluations. We will randomise 512 women with early-stage breast cancer who have been prescribed AET to one of sixteen experimental conditions, operationalised as factors with two levels (on/off). Each condition is comprised of unique combinations of the intervention components. All participants will receive usual care. Our primary outcome is self-reported medication adherence at 12 months post-randomisation. Key secondary and process outcomes include quality of life, self-efficacy, habit formation, medication beliefs, psychological flexibility and distress, completed at 4, 8 and 12 months post-randomisation. Within the process evaluation, semi-structured interviews with participants will be conducted 5 and 13 months post-randomisation, and with trial therapists following intervention delivery. Cost per incremental quality-adjusted life year will be estimated in a health economic evaluation.</p> Discussion <p>Within the optimisation phase of the MOST framework, this trial, using a complex factorial design, will enable us to build a more effective, affordable, scalable and efficient intervention package to support AET adherence in women with breast cancer. This approach will advance intervention science by simultaneously testing the mechanisms through which the intervention components are operating.</p> Trial registration <p>International Standard Randomised Controlled Trial Number ISRCTN17334319. Registered on 02/02/2024.</p>