Objectives: This study aims to determine the factors associated with absenteeism, presenteeism, and overall work impairment in patients with systemic lupus erythematosus (SLE). Methods: A total of 133 consecutive working patients with SLE were assessed between October 2017 and December 2018, using a standardized data collection form. Sociodemographic, disease, and work-related variables were collected. Work productivity and activity impairment (WPAI) was assessed with the respective questionnaire; absenteeism and presenteeism due to overall health and symptoms during the past 7 days were scored. Linear regression models were performed to determine the factors associated with absenteeism, presenteeism, and overall work impairment. Potential factors included were age at diagnosis, gender, socioeconomic status, educational level, SLEDAI, SLICC/ACR damage index (SDI), FACIT-Fatigue, and the domains of the LupusQoL Results: The mean age at diagnosis was 32.2 years (11.8); 121 (91.7%) were female. Nearly all patients were Mestizo. The mean percent of time for absenteeism was 5.0 (12.9), it was 28.5 (26.4) for presenteeism, and it was 31.3 (27.2) for overall work impairment. In the multiple regression analysis, factors associated with absenteeism were disease duration (B = −0.34; SE = 0.12; p = 0.007), pain (B = −0.14; SE = 0.06; p = 0.046), intimate relationship (B = −0.07; SE = 0.03; p = 0.046), and emotional health (B = 0.16; SE = 0.06; p = 0.006); factors associated with presenteeism were physical health (B = −0.43; SE = 0.14; p = 0.002) and FACIT (B = −0.87; SE = 0.30; p = 0.005); and factors associated with overall work impairment were pain (B = −0.40; SE = 0.11; p = 0.001) and FACIT-Fatigue (B = −0.74; SE = 0.28; p = 0.010). Conclusion: A poor HRQoL and higher levels of fatigue were associated with a higher percentage of absenteeism, presenteeism, and overall work impairment in SLE patients.