The effect of prednisone therapy on plasma lipoproteins and apolipoproteins A-I, A-II, and E levels was studied prospectively in a heterogeneous group of six male and six female subjects. All patients were in a good general condition. The patients had normal hepatocellular, renal, and thyroid functions. During the first month of therapy, the following changes were noted: Plasma triglyceride (TG) levels increased slightly in female patients only. In the entire group, plasma cholesterol level increased (17.3% of initial value, P less than 0.01). Plasma high-density lipoprotein cholesterol (HDL-C) level increased by 68% (P less than 0.001), while plasma low-density lipoprotein cholesterol (LDL-C) level increased by only 10.9% (not significant), resulting in an increased ratio of cholesterol in the two (P less than 0.01). No change in levels of plasma apolipoproteins A-I, A-II, and E was evident. The ratio of HDL-C to plasma apolipoprotein A-I increased (P less than 0.01), indicating an increased lipid to protein ratio for this lipoprotein. Most of these changes were already apparent and significant 48 hours after initiation of treatment and persisted throughout the follow-up period (up to 18 months in some patients). Our results show that in patients with no major metabolic abnormality, prednisone induces significant changes of the lipoprotein system, especially in HDL.