Background: The multisystem manifestations of Systemic lupus erythematosus (SLE) greatly affect the patients, physical and psychological functioning, and impair their capability to take part in work and social activities. This study aimed to explore SLE disease activity, severity and fatigue impacts on patients’ quality of life (Qol). Methods: We conducted this cross-section study on 84 SLE patients who were defined as having SLE by the criteria established by the American College of Rheumatology (ACR) in its most recent revision. Assessment of fatigue factors was done via the multidimensional assessment of fatigue (MAF) questionnaire. Disease activity was assessed by Systemic Lupus Disease Activity Score (SLEDAS). Severity of disease was assessed by Lupus Severity Index (LSI). QoL of the SLE cases was evaluated by the Arabic version of SLE QoL questionnaire. Results: The mean SLEDAS was 16.64±13.59 with (85.7%) of cases had High Lupus Disease Activity Score (HLDAS) and the others (14.3%) had Low Lupus Disease Activity Score (LLDAS). The mean SLEQoL score was 105.69±32.37 and the mean MAF score was 57.24±28.17. Statistically significant differences were found between lupus patients with HLDAS and those with LLDAS as regards fatigue and QoL. Patients with HLDAS group showed higher mean scores of MAF and SLEQoL while no statistically significant differences were found between patients with HLDAS and those with LLDAS as regards age, duration of disease and LSI. Conclusion: Inter-relationships between assessment indices of activity, severity, fatigue and QoL were studied and revealed strong positive correlations between MAF and both SLEQoL SLEDAS. There was a moderate positive correlation between SLEDAS and SLEQoL. There were weak positive correlations between LSI and each of indices (SLEQoL, SLEDAS and MAF). Multivariate logistic regression revealed that MAF was only significant associated factor with SLE disease activity