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Systemic lupus erythematosus (SLE) is one of the leading causes of death in younger adults, but advances in diagnosis and management during recent years may have reduced mortality. We examined whether SLE is a leading cause of death in Mexico among females. Data for death counts for the female population were obtained from the General Board of Health Information (DGIS) Open Access datasets, which evaluate death certificates, from 2000 to 2020. SLE was defined using the Tenth Revision of the International Classification of Disease codes: M32.1, M32.8, and M32.9. From 2000 to 2020, there were 12,114 deaths of females with SLE recorded as an underlying cause of death in Mexico. SLE ranked among the top 20 leading causes of death in females aged 10–54 years. SLE ranked fifteenth for deaths in people aged 15–24 years, sixteenth in those aged 25–34 years and 35–44 years, and eighteenth in those aged 45–54 years. After three frequent external injury causes of death were excluded from the analysis, focusing on the organic causes of death, SLE ranked twelfth in those aged 15–24 years and thirteenth in those aged 25–34 years and 35–44 years. In Mexico, SLE is among the leading causes of death in young females, emphasizing its significance as a public health issue.