We conducted an open-labeled, prospective study to determine the efficacy and safety of tacrolimus as an alternative therapeutic option for those patients with refractory lupus nephritis. The study population comprised one male and eight female patients with diffuse proliferative lupus nephritis. All patients had failed to respond to sufficient intravenous cyclophosphamide therapy with proteinuria of >or=1 g/day and active urinary sediments. Tacrolimus (0.1 mg/kg/day) was administered for 1 year with adjusting drug level (4-10 microg/l). The mean serum creatinine level and spot urine protein creatinine ratio (UPCR) at baseline were 1.39 mg/dl and 2.27, respectively. After the treatment, proteinuria reduced significantly from median UPCR value of 2.19 (range, 1.19-3.34) to 0.44 (range, 0.12-2.13) (p < 0.05). Seven (78%) of the nine patients showed a complete clinical response, which was defined as stabilization in the disease-activity markers and serum creatinine level with reduction of >or=50% in UPCR; two patients showed complete remission with UPCR <0.2. One patient showed treatment failure because of the disease progression. No serious adverse effects were observed during the study. This study demonstrates that tacrolimus can show a significant therapeutic response in cases that are refractory to the standard regimen for diffuse proliferative lupus nephritis.