BACKGROUND: Systemic lupus erythematosus (SLE or lupus) is a chronic autoimmune disease that is associated with increased morbidity, mortality, healthcare costs and decreased quality of life. African Americans in the USA have three to four times greater prevalence of SLE, risk of developing SLE at an earlier age, and SLE-related disease activity, damage, and mortality compared with Caucasians, with the highest rates experienced by African American women. There is strong evidence that patient-level factors are associated with outcomes, which justifies targeting them with intervention. While evidence-based self-management interventions that incorporate both social support and health education have reduced pain, improved function, and delayed disability among patients with SLE, African Americans and women are still disproportionately impacted by SLE. Peer mentoring interventions are effective in other chronic conditions that disproportionately affect minorities, such as diabetes mellitus, HIV, and kidney disease, but there is currently no empirically tested peer mentoring intervention developed for patients with SLE. Preliminary data from our group suggest that peer mentoring improves self-management, reduces disease activity, and improves health-related quality of life (HRQOL) in African American women with SLE. METHODS: This study will test an innovative, manualized peer mentorship program designed to provide modeling and reinforcement by peers (mentors) to other African American women with SLE (mentees) to encourage them to engage in activities that promote disease self-management. Through a randomized, "mentored" or "support group" controlled design, we will assess the efficacy and mechanism(s) of this intervention in self-management, disease activity, and HRQOL. DISCUSSION: This is the first study to test peer mentorship as an alternative strategy to improve outcomes in African American women with SLE. This could result in a model for other programs that aim to improve disease self-management, disease activity, and HRQOL in African American women suffering from chronic illness. The peer mentoring approach is uniquely fitted to African Americans, and this intervention has the potential to lead to health improvements for African American women with SLE that have not been attainable with other interventions. This would significantly reduce disparities and have considerable public health impact. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03734055 . Registered on 27 November 2018.