BACKGROUND: In the Pakistani textile industry the prevalence of workplace respiratory illnesses, including byssinosis, is high. The MultiTex RCT study aims to determine the effectiveness of a multifaceted intervention package in reducing dust levels in cotton mills, decreasing the frequency of respiratory symptoms among cotton textile workers, and improving their lung function. METHODS/DESIGN: We will conduct a cluster-randomized controlled trial at 28 textile mills in Karachi. The intervention will comprise: training in occupational health for all workers and managers reinforced by regular refresher sessions; the formation of workplace committees to draw up, agree and promote a health and safety plan that includes wet mopping, safe disposal of cotton dust, and the use of simple face-masks, as well as further publicity about the risks from cotton dust; and provision of adequate supplies of face-masks to support the health and safety plan. Participating mills will be randomized to intervention and control arms following a baseline survey. The impact of the intervention will be determined through follow-up surveys conducted at 3, 12 and 18 months. Data collection in the surveys will include spirometry, questionnaire-based interviews and cotton-dust measurements. DISCUSSION: If successful, the study may pave the way for simple, low-cost interventions that can help reduce cotton-dust levels in textile mills, and improve the respiratory health of textile workers in developing countries such as Pakistan. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03738202. Registered on 12 November 2018.