OBJECTIVE: To prospectively identify factors influencing quality of life (QOL) over 6 months in patients with systemic lupus erythematosus (SLE). METHODS: Ninety ethnically diverse patients with SLE completed questionnaires administered 6 months apart assessing QOL (using the Medical Outcomes Study Short Form-36) and demographic, socioeconomic, psychosocial, and behavioral factors. Disease activity, damage, and treatment were recorded at both evaluations. Multiple linear regression (adjusting for baseline health status) was used to identify factors influencing mental and physical health. RESULTS: Improved physical health after 6 months was associated with reductions in learned helplessness (p = 0.034), improved mental health (p<0.001), longer disease duration (p = 0.009), and better physical health at baseline (p = 0.027). Improved mental health after 6 months was associated with better family support (p = 0.002), improvements in physical health (p<0.001), disease activity, and prednisolone dose (interaction term p = 0.019), less disease related damage (p<0.001), non-use of cytotoxic drugs (p = 0.02), and older age at diagnosis (p = 0.007). CONCLUSION: Potentially modifiable psychosocial, disease, and therapy related factors influence QOL in patients with SLE.