Background/Purpose: To describe cumulative organ damage in a longitudinal cohort of SLE patients and to assess the impact of key disease-related factors, medication, demographic variables, and serologic markers on the incidence of damage. The relationship between cumulative organ damage and health-related quality of life was also examined. Methods: A longitudinal database of SLE patients with up to 14 years of follow-up was analyzed. Patients were assessed for (i) cumulative organ damage (Systemic Lupus Erythematosus International Collaborative Clinic (SLICC)/ACR’s Damage Index (SDI)) and (ii) health-related quality of life (Medical Outcomes Survey Short Form 36 (SF-36) subscale and summary scores) at inclusion and annually thereafter. The impact of demographic, disease-related and treatment-related factors on impairment progression was investigated using multivariate Cox proportional risk models. the impact of changes in SDI scores on health-related quality of life was also assessed using linear mixed-effects models. Results: A total of 273 patients with SLE had a mean (SD) follow-up of up to 7.3 (4.3) years. Seventy-seven patients (28.2%), had pre-existing impairment (baseline SDI > 0) and 126 (46.1%) patients had increased SDI scores during the follow-up period. Multivariate analysis showed that older age, eight or more ACR classification criteria, use of immunosuppressive drugs, smoking and higher levels of C-reactive protein (CRP) up to the time of the first SDI change were associated with increased SDI scores. Changes in SDI scores were associated with initial changes in SF-36 scores when impairment occurred and there was a subsequent change in patient health-related quality of life compared to patients without impairment progression. CONCLUSIONS: Additional damage in SLE patients is predicted by the preexistence of some variable risk factors such as organ damage. The damage process has a negative impact on health-related quality of life, so it is necessary to develop effective prevention and treatment strategies for variable risk factors to reduce organ damage.