The aim of this study was to examine the independent and interactive associations among body mass index (BMI), disease activity, on health-related quality-of-life (HRQoL) in Chinese patients with systemic lupus erythematosus (SLE). Three hundred eighty-four patients with SLE were recruited in this study. The investigations were conducted by the Short Form-36 (MOS SF-36) questionnaire. Disease activity was assessed by the SLE disease activity index (SLEDAI). The regression analyses were used to identify independent and interactive associations that were associated with the PCS and MCS. The presence of psychological morbidity was associated with all the scores from SF-36. In multivariable analyses, The physical (PCS) and mental (MCS) component summary scores of MOS SF-36 were negative correlation with BMI and SLEDAI; BMI was independently associated with PCS and MCS but not with disease activity. However, the interactive association of BMI and SLEDAI on HRQoL was negligible. An increased BMI and SLEDAI are independently associated with quality-of-life in patients with SLE. Optimizing weight merits investigation to see if it can significantly improve the HRQoL of SLE patients.