Objective: To define the factors associated with fatigue in Mestizo patients with Systemic Lupus Erythematosus (SLE). Methods: This is a cross-sectional study of SLE patients from a single center cohort. Visits were performed every six months. For these analyses, the first visit between October 2017 and December 2018 was included. Demographic and clinical characteristics as well as treatment were recorded at every visit. Fatigue was ascertained with the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-FT), Health-Related Quality of Life (HRQoL) with the LupusQoL, disease activity with the Systemic Lupus Erythematosus Disease Activity Index –2 K (SLEDAI-2K), and damage with the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology damage index (SDI). Prednisone use was recorded as current daily dose. Immunosuppressive drugs and antimalarial use were recorded as current, past or never. Univariable and multivariable analyses were performed using linear regression models. For the multivariable analyses, model selection followed a backward elimination procedure. Results: Two hundred and twenty-six patients were evaluated. The mean (SD) age at diagnosis was 35.6 (13.1) years, 211 (93.4%) were female; and disease duration was 11.0 (7.3) years. The mean SLEDAI and SDI were 2.4 (3.5) and 1.3 (1.5), respectively. The mean FACIT-FT was 33.1 (10.8). On the multivariable analysis, age at diagnosis and some domains of HRQoL (physical health, emotional health and fatigue) remained associated. Conclusions: Age at diagnosis is negatively associated with fatigue whereas HRQoL domains like physical health, emotional health and fatigue are positively associated with fatigue.