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Background and Objective: Neuropsychiatric disorders including depression are common clinical manifestations of systemic lupus erythematosus (SLE). Depression in patients with SLE is under-recognized, although it is a treatable clinical entity. The present study aimed to determine the prevalence of depression and identify the relationship between depression and SLE disease characteristics. Patients and Methods: This multicenter cross-sectional study was conducted in the rheumatology clinics of four tertiary referral hospitals in Saudi Arabia between April and September 2014. Patients' demographic data and SLE disease characteristics such as disease duration, severity and drug treatments were collected. A validated Arabic Beck Depression Inventory (BDI) score was used to estimate the prevalence of depression. Results: A total of 68 patients with SLE (64 women, 4 men) were enrolled in the study. Forty-six (67.6%) patients were found to have BDI scores indicating depression; of them, only four patients (8.7%) were receiving antidepressant treatments. Higher prevalence of depression was associated with steroid treatment (P = 0.046). Conclusions: The study results revealed high prevalence of depression among Saudi patients with SLE. Most of the study population were not adequately treated, suggesting inadequate recognition and treatment of depression in SLE.