The present study was performed to evaluate the potential protective effects of Shikonin extracted from Zicao on lupus nephritis (LN) using NZB/W F1 mice. Oral administration of Shikonin (24, 40 mg/kg body weight/d) or vehicle was applied to sixty female NZB/W F1 mice of 28-week-old with LN. Treatment with Shikonin for 14 weeks suppressed proteinuria dose-dependently with the mean proteinuria of 274.0 mg/dl and 160.3 mg/dl for low-dose and high-dose Shikonin groups, respectively, compared to 499.2 mg/dl for the vehicle. Also, Shikonin was observed to reduce circulating adhesion molecules significantly and down-regulate intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) mRNA expression in kidney. However, anti-double stranded (ds)DNA antibody in mice with low or high Shikonin dose administration both exhibited no significant elevation, differing from vehicle group. Kidney histological examination showed that renal glomerular lesions were alleviated after Shikonin application. These results suggest that Shikonin has therapeutic effects on LN in NZB/W F1 mice, to which inhibition of anti-dsDNA may be potential contribution, and its part mechanism is related to suppression of mRNA expression of cell adhesion molecules (CAMs) in the kidney.