Hydroxychloroquine has been suggested to exert lipid lowering effects. The purpose of this study was to determine the effect of hydroxychloroquine on total cholesterol and on other lipoproteins in a controlled trial involving patients with systemic lupus erythematosus (SLE). Seventeen female patients with SLE were enrolled in a double-blind, randomized, placebo-controlled, multiple-dose pilot study comparing placebo with hydroxychloroquine at daily doses of 400 and 800 mg. The primary endpoint was alteration in total cholesterol. Patients were evaluated at two screening visits pretreatment and at three monthly follow-up visits. At all visits, a fasting panel of lipoproteins, disease activity, and adverse drug effects were assessed. There were no significant alterations in lipoproteins in patients receiving placebo. Treatment with 400 mg/day of hydroxychloroquine resulted in a significant decrease in total cholesterol (mean decrease of 11.6 mg/dL). Treatment with 800 mg/day of hydroxychloroquine resulted in a significant decreases in total cholesterol (mean decrease of 13.4 mg/dL), triglycerides, very low density lipoproteins, cholesterol, and the ratios of total cholesterol/high density lipoprotein cholesterol and low density lipoprotein/high density lipoprotein cholesterol. More adverse effects were noted among patients receiving the high dose (800 mg/day). Hydroxychloroquine affects a significant reduction in total cholesterol in patients with SLE. The findings of this double-blind, placebo-controlled, pilot trial support the conclusions of earlier open trials. This lipid-lowering effect may be an added benefit of hydroxychloroquine treatment in these patients with a high prevalence of atherosclerotic cardiovascular disease.