Background: Pediatric SLE (pSLE) patients suffer from enhanced morbidity and hence poor health related quality of life (HRQOL), and this is expected to be more pronounced in developing countries. Objective: We sought to objectively evaluate the impact of pSLE on the health-related quality of life (HRQOL) in relation to disease activity and organ involvement aiming to aid strategies of improving quality of life (QOL) of those patients and their families. Methods: This is a cross-sectional analytical study. We enrolled 60 subjects with pSLE from the Pediatric Allergy, Immunology and Rheumatology Unit, Children's Hospital, Ain Shams University, Cairo. They were subjected to HRQOL assessment using the SLE specific QOL (SLEQOL) scales which encompass 40 items comprising physical functioning, activities, symptoms, treatment, mood, and self-image. The higher the total score the worst is the HRQOL of the patient. We also used the SMILEY scoring questionnaire, which consists of 26 items for children with SLE up to 18 years of age, in assessment of the patients' QOL. Results: The patients' ages ranged between 12-18 years (mean ± SD = 12.2 ± 1.9 years); 57 were females and 3 were males. All domains of the SLEQOL were significantly altered in patients evaluated during disease activity. The SMILEY scores, as well, were significantly affected by disease activity and correlated positively to the total SLEQOL score results. Most of our series (59 out of 60) had lupus nephritis, 31 (51.7%) had lupus arthritis, 12 (20.0%) had lupus carditis, and 5 (8.3%) had lupus cerebritis. The SLEQOL score in patients with lupus nephritis and arthritis were comparable (142.86 ± 33.74 and 143.1 ± 33.34 respectively). The scores were worse in lupus cerebritis and carditis (158.6 ± 49.9 and152.75 ± 39.98, respectively). Conclusion: We observed a significant impact of pSLE on the HRQOL especially during disease activity. Patients with lupus cerebritis and carditis had the worst QOL status and this might be related to the physical impairment and/or intensity of immunosuppressive medications. Wider-scale prospectively designed studies would better validate our conclusions. HRQOL assessment should be implemented in the care of pSLE patients on regular basis.