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Introduction Thromboembolic events are an important cause of morbidity and mortality in systemic lupus erythematosus (SLE). Current thromboprophylaxis recommendations mainly focus on patients with antiphospholipid syndrome or persistent antiphospholipid antibody (aPL) positivity, whereas preventive strategies for aPL-negative patients with elevated thrombotic risk remain poorly defined. D-dimer elevation is common in SLE and has been associated with an increased risk of venous thromboembolism (VTE), but its role in guiding preventive anticoagulation remains uncertain.Methods and analysis PREVENT-SLE is a multicentre, prospective, open-label, randomised controlled trial designed to compare rivaroxaban with aspirin for the primary prevention of VTE in persistently aPL-negative patients with SLE at elevated thrombotic risk. A total of 456 adult participants meeting predefined high-risk criteria, defined as D-dimer >2.0 µg/mL or SLE-VTE score ≥100, will be randomly assigned in a 1:1 ratio to receive rivaroxaban 10 mg one time per day or enteric-coated aspirin 100 mg one time per day for 12 months. The primary endpoint is time to the first objectively confirmed VTE event. Secondary outcomes include arterial thrombotic events, major bleeding, all-cause mortality and longitudinal changes in disease activity. The primary analysis will follow the intention-to-treat principle. Kaplan–Meier curves, log-rank tests and Cox proportional hazards models will be used to compare treatment effects between groups.Ethics and dissemination The study has been approved by the Biomedical Research Ethics Committee of the Second Xiangya Hospital, Central South University (approval number: LYEC2025-K0180) and will be conducted in accordance with the Declaration of Helsinki. The findings will be disseminated through peer-reviewed publication and academic conferences.Trial registration number ChiCTR2600117175.