Twelve systemic lupus erythematosus (SLE) patients with mild to moderate disease activity (SLEDAI of ≥6 and on prednisolone, 0.5 mg/kg/day) were included in a prospective, randomized, double-blind, placebo-controlled pilot study for 24 weeks. Six were randomized to receive oral leflunomide and six received placebo. Primary outcome of this study included the mean change of SLEDAI at 24 weeks. Secondary outcomes included the changes in proteinuria, complement levels, anti ds-DNA binding, and prednisolone dosage. The mean age of the 12 patients was 41 + 9 years, and the mean disease duration was 8.5 + 5.8 years. All were female except one patient. The disease activity of both groups of patients decreased significantly after six months of treatment (14.7 + 6.0 to 3.7 + 2.3 in leflunomide group, P ¹/4 0.028, and 9.7 + 3.4 to 5.2 + 4.1 in placebo group, P ¹/4 0.027). Reduction in the SLEDAI from baseline to 24 weeks was significantly greater in the leflunomide group than the placebo group (11.0 + 6.1 in the leflunomide group and 4.5 + 2.4 in the placebo group respectively, P ¹/4 0.026). Minor adverse events included transient elevation in ALT, hypertension and transient leucopenia. In summary, leflunomide was more effective than placebo in treating SLE patients with mild to moderate disease activity and was safe and well-tolerated.