Objective: In this paper, we aim to define factors associated with health-related quality of life (HRQoL) in Mestizo patients with systemic lupus erythematosus (SLE). Methods: We evaluated patients with SLE from Peru’s two largest hospitals between October 2012 and July 2015 to ascertain HRQoL. Using a standard protocol, we incorporated demographic characteristics, clinical manifestations and treatment in our analysis. HRQoL was measured with the LupusQoL, disease activity was ascertained with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and damage was appraised with the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) damage index (SDI). The associations between the LupusQoL and these variables were examined using linear regression models. Model selection was based on backward elimination. Results: A total of 277 patients fit the inclusion criterion. Of these, 254 (91.7%) were female, the median (interquartile range, IQR) age at diagnosis was 41.5 (33.8–51.8) years, disease duration was 6.5 (2.7–11.3) years. The HRQoL domains most affected were the following: burden to others, fatigue, and intimate relationships. Through multivariate analysis, we determined that older age at diagnosis, higher disease activity, damage, and immunosuppressive drug use were negatively associated with HRQoL. Further, we found that higher socioeconomic status, disease duration, and antimalarial use were positively associated with HRQoL. Conclusion: Age at diagnosis, disease activity, damage, and use of immunosuppressive drugs were negatively associated with HRQoL; high socioeconomic status, disease duration, and use of antimalarials were positively associated with HRQoL.