Monolayer cultures of normal human fibroblasts were used to study the effects of the main subclasses of high-density lipoproteins, HDLa and HDL3, on 3-hydroxy-3-methylglutaryl CoA reductase (EC 1.1.1.34) activity. In this system, HDL3 (d= 1.125–1.210 g/cm3) specifically induced HMG-CoA reductase activity. Evaluation of culture dynamics revealed that enzyme induction was restricted to the stationary phase of growth. When the cells were incubated with HDL2 (d = 1.063–1.125 g/cm3), suppression of reductase activity was observed. Mixtures of HDL2 and HDL3 suppressed reductase activity when HDL2 was greater than 35% of the total HDL. The suppressive effects of HDL2 were abolished by treatment with cyclohexanedione and restored by regeneration of the arginyl residues, suggesting an apoprotein-mediated suppressive mechanism. These observations show that the cellular effects of HDL depend upon the stage of cell growth and the ratio of HDL subclasses in HDL as usually isolated.