Background: Flares in patients with SLE, regardless of their severity, have been associated with damage accrual. However, their impact on health-related quality of life (HRQoL) has not been fully evaluated. In fact, disease activity is only minimally associated with HRQoL. Objective: To determine the association between flares and HRQoL. Methods: Patients from the Almenara Lupus Cohort were included. Visits occurring between December 2015 and February 2020 were evaluated. Flares were defined as an increase on the SLE Disease Activity Index 2000 (SLEDAI-2K) of at least 4 points; severe flares were those with a final SLEDAI-2K ≥12 and mild-moderate flares all the others. HRQoL was measured using the LupusQoL. Univariable and multivariable generalised estimating regression equations were performed, adjusting for possible confounders. Confounders were determined at one visit, whereas the outcome was determined on the subsequent visit; flares were determined based on the variation of the SLEDAI-2K between these visits. Results: Two hundred and seventy-seven patients were included; 256 (92.4%) were female, mean age at diagnosis was 36.0 (SD: 13.3) years and mean disease duration at baseline was 9.1 (SD: 7.1) years. Patients had mean of 4.8 (SD: 1.9) visits and a mean follow-up of 2.7 (1.1) years. Out of 1098 visits, 115 (10.5%) flares were defined, 17 were severe and 98 mild-moderate. After adjustment for possible confounders, only severe flares were associated with a poorer HRQoL in planning, pain, emotional health and fatigue. Conclusions: Severe flares, but not mild-moderate, flares are associated with poorer HRQoL.