The aim of this study was to compare the mRNA and serum expression of tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) in patients with systemic lupus erythematosus (SLE) and healthy controls. Sixty-two SLE patients and 15 healthy controls were recruited in the study. TWEAK messenger RNA (mRNA) expression in peripheral blood mononuclear cells (PBMCs) from 33 of 62 patients was detected by relative quantification RT-PCR. TWEAK concentrations in the sera of all 62 patients were measured by ELISA. TWEAK mRNA expressions in PBMCs were decreased in SLE patients compared with healthy controls. Lower TWEAK mRNA expression was also found in the active SLE patients when compared to inactive ones. However, there was no significant difference between patients with lupus nephritis (LN) and those without. The level of serum TWEAK (sTWEAK) in SLE patients was increased when compared to healthy controls. In addition, the sTWEAK level was higher in SLE patients with vasculitis than those without vasculitis, and so was in comparison between patients with and without headache. Nevertheless, no significant differences were found between active SLE patients and inactive patients, or between LN patients and non-LN SLE patients. In this study, patients with SLE express low levels of TWEAK mRNA but high levels of sTWEAK. Additionally, sTWEAK level was associated with several clinical manifestations of SLE, indicating that TWEAK may play a complex role in SLE.