INTRODUCTION: Mycobacteroides abscessus (MABS) is within the non-tuberculous mycobacteria family. It inhabits soil and water, exhibits multi-antibiotic resistance and causes opportunistic lung infections, which may progress to symptomatic MABS-pulmonary disease (MABS-PD) associated with substantial morbidity, increased healthcare utilisation, impaired quality of life and increased mortality. Treatment regimens for MABS-PD are highly variable, not evidence-based and involve complex, expensive drug combinations administered for prolonged periods (>12 months) with frequent adverse effects and treatment failure. There is an urgent need for safe, efficacious and cost-effective MABS-PD therapy. Here, we describe the Master Protocol for the Finding the Optimal Regimen for Mycobacteroides abscessus Treatment (FORMaT) trial. FORMaT aims to determine the most effective and best tolerated treatment for MABS-PD as defined by MABS clearance from respiratory samples with good treatment tolerance. METHODS AND ANALYSIS: FORMaT is an international multicentre, adaptive platform trial evaluating treatment combinations for MABS-PD. Participants are randomised multiple times during the trial, with assessment of the primary outcome of clearance of MABS infection with good treatment tolerance. Initially, therapies recommended in international consensus guidelines are being tested. Data obtained will eliminate therapies lacking efficacy or causing unacceptable toxicity. Novel treatments can then be added and tested against previously determined optimal approaches, leading in an iterative fashion to improved microbiological clearance and health outcomes. In parallel, an Observational cohort and several integrated and discovery studies are embedded in FORMaT to identify biomarkers of MABS-PD and MABS clearance, clinical and radiographic treatment response, drug pharmacokinetics and Mycobacteroides genomics and resistome. ETHICS AND DISSEMINATION: The FORMaT Master Protocol and related documents are approved by regulatory authorities in each participating jurisdiction and/or site. Results will be published in peer-reviewed journals and presented at scientific meetings. De-identified, aggregated data will be shared on an approved online platform. TRIAL REGISTRATION NUMBERS: NCT04310930, ANZCTR12618001831279, 2020-000050-10, ISRCTN67303903.