question: Systemic Lupus erythematosus (SLE) is a chronic multisystem, multifactorial inflammatory autoimmune disease. The SLE patients have 3 times increased risk of mortality based on international data with ethnicity playing an important impact on patients’ morbidity and mortality. Descriptive studies from Saudi Arabia showed variation in clinical features from one region to another. Moreover, reliable inference from these studies is limited by study methodology and lack of translational data using biological samples to understand clinical phenotypes of Saudi SLE patients. The aim of this report is to describe the prospective study protocol of the National Systemic Lupus Erythematosus Cohort in Saudi Arabia. The purpose of this cohort study is multifold: first, to examine clinical characteristics and molecular phenotypes of Saudi SLE patients in relation to local environment and practices/lifestyles; second, to assess long-term outcomes of SLE in Saudi population and factors that influence favorable outcomes; third, to compare the effectiveness of various treatment regimens in Saudi SLE population. This study is a longitudinal prospective cohort study of adult, Saudi SLE patients using open cohort study design. Primary outcomes include disease-related outcomes (activity, improvement, and organ damage) and patient-reported outcomes (quality of life). Secondary outcomes include physiological and molecular modifications associated with changes in disease activity states.Results and analysis are in on-going study. This study provides a source of reliable data for clinical and translational research. This will allow us to have a holistic approach to SLE pathogenesis especially in Saudi population and may take us a step further toward much more personalized medicine. This protocol has been registered in NIH ClinicalTrial.gov (ClinicalTrial.gov identifier: NCT04604990) on October 27, 2020.