Objective. To determine the factors associated with increased levels of fatigue over the course of the disease in systemic lupus erythematosus (SLE) patients from LUpus in MInorities: NAture versus nurture, a longitudinal multiethnic cohort. Methods. Patients with SLE (according to the American College of Rheumatology revised and updated criteria) age ≥16 years with a disease duration ≤5 years at entry into the cohort, and of Hispanic (Texan or Puerto Rican), African American, or Caucasian ethnicity were studied. The association between socioeconomic/demographic characteristics, health behaviors, behavioral and psychological, functional and clinical characteristics, and fatigue was examined using generalized estimating equations to account for the longitudinal nature of the data. Results. A total of 515 patients (∼91% female) contributed 2,609 visits to these analyses. Of these patients, 93 (18.1%) were Texan-Hispanic, 101 (19.6%) were Puerto Rican-Hispanic, 169 (32.8%) were African Americans, and 152 (29.5%) were Caucasian. The mean ± SD patient age and followup time were 37.2 ± 12.6 years and 4.7 ± 3.2 years, respectively. Variables associated with increased levels of fatigue in the multivariable analyses were Caucasian ethnicity, the presence of constitutional symptoms (fever, weight loss), and higher levels of pain, abnormal illness-related behaviors, and helplessness (P values between 0.0018 and <0.0001). Conclusion. The presence of pain, abnormal illness-related behaviors, helplessness, and constitutional manifestations were associated with increased levels of fatigue. However, SLE-specific measures, such as disease activity and damage, were not. Interventions aimed at decreasing fatigue need to take into account these findings. © 2009, American College of Rheumatology.