We have examined the effect of estrogen on the rate of accumulation of apolipoproteins secreted by the human hepatocarcinoma cell line, HepG2. Prior to exposure to hormone, we detected less than 300 high-affinity, nuclear, estrogen-binding sites/cell. Within 48 h of growth in the presence of 20 nM 17 beta-estradiol this number rose to 3000-3500 sites/cell. Rates of accumulation of two of the major apolipoproteins, apo-C-II and apo-A-I increased 2.5- and 2.0-fold, respectively, in response to estrogen treatment. Other major apolipoproteins were not affected at this concentration of hormone. Induction of both proteins was completely antagonized by 20 nM testosterone. The density distribution of apolipoproteins secreted by the hepatocytes was similar to that reported using perfused liver systems. The consequences of estrogen treatment were to increase the apo-C-II/apo-C-III ratio in very low density lipoproteins as well as to decrease the overall very low density lipoprotein:high density lipoprotein ratio.