This study was designed to examine the potential use of the ethyl acetate (EA) extract of Tripterygium wilfordii Hook F (TwHF), a Chinese herbal medicine, in the treatment of systemic lupus erythematosus. A total of 48 28-week-old female NZB/W F1 mice were randomly divided into three groups and orally administered vehicle or the EA extract of TwHF at 18.25 mg/kg (EAlow) or 36.5 mg/kg (EAhigh) for 14 weeks. Proteinuria and serum anti-double-stranded (ds)DNA antibody titers were assayed before and after treatment. At the end of treatment, all animals were sacrificed and pathological changes in the kidneys were examined by observers blinded to the treatment regimens. Immunohistological studies were carried out on kidneys and spleens. At 28 weeks of age, proteinuria (>30 mg/dl) and anti-dsDNA antibodies were found in all mice in the three groups. Fourteen, sixteen and fifteen mice in the vehicle, EAlow and EAhigh groups, respectively, completed at least four weeks of treatment. At the end of treatment, the mean proteinuria of the EAlow and EAhigh groups was significantly less than that of the vehicle group and no different from proteinuria at the onset of treatment. Histological evidence of glomerulonephritis, glomerular deposition of IgG and complement 3 and cellular infiltration in the interstitium and perivascular regions were significantly less severe in the EA extract treated mice than in vehicle treated mice. Treatment with the EA extract significantly inhibited the progression of kidney disease in NZB/W F1 mice, though had no significant effect on the levels of anti-dsDNA antibody.