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Objectives: It is important to clarify the relationship between irreversible organ damage and the quality of life (QOL) by considering the unique factors of patients with systemic lupus erythematosus (SLE). We aimed to clarify their correlation using SLE-specific QOL assessment tools. We also aimed to identify which type of organ damage is adversely correlated with the QOL. Methods: We conducted a questionnaire-based survey of outpatients with SLE at Kyoto University Hospital and evaluated irreversible organ damage using the SLICC/ACR damage index (SDI). LupusPRO and the SLE symptom checklist (SSC) were employed as SLE-specific QOL tools, and the SF-36v2 was used as a conventional QOL tool. Multiple linear regression analyses were performed to examine the correlations between the total SDI score and each QOL score, and between each SDI item/system score and each QOL score. Results: We analyzed the data of 265 patients. The total SDI score was significantly correlated with physical (PCS) and role/social component summary (RCS) of the SF-36v2, health-related QOL (HRQOL) of LupusPRO, and SSC (p < 0.001). Among the SDI items, atrophy/weakness and osteoporosis with fracture/vertebral collapse were negatively correlated with PCS (β = −0.40, p < 0.001/β = −0.28, p < 0.001), RCS (β = −0.30, p < 0.001/β = −0.35, p < 0.001), and HRQOL (β = −0.34, p < 0.001/β = −0.31, p < 0.001), respectively. Among the SDI systems, musculoskeletal damage had higher negative correlations with PCS (β = −0.51, p < 0.001), RCS (β = −0.29, p < 0.001), and HRQOL (β = −0.40, p < 0.001). Conclusion: We demonstrated the QOL of patients with SLE is negatively correlated with irreversible organ damage. We also revealed musculoskeletal damage is adversely correlated with the health-related QOL, especially the physical and role/social QOL. [ABSTRACT FROM AUTHOR]