The human hepatoblastoma line Hep G2 modulates gene expression in vitro in response to increasing culture density. Two stages of growth can be defined. At low density (less than 200,000 cells/cm2) the cultures have a doubling time of 24 h and exhibit several characteristics of fetal liver cells, including increased synthesis of alphafetoprotein, reduced synthesis of albumin, a predominance of the fetal isoenzymes of both aldolase and pyruvate kinase and a reduced level of the cell surface receptor for asialoglycoproteins. Confluent, high density cultures of Hep G2 (greater than 1 X 10(6) cells/cm2) have a doubling time of 193 h, a four fold higher level of albumin production, increased levels of the adult isoenzymes of aldolase and pyruvate kinase and increased asialoglycoprotein receptor. The alteration in albumin and alphafetoprotein synthesis was reflected by changes in the messenger RNA levels and the relative transcription of these two genes. Hep G2 provides a cell culture model for the modulation of the liver phenotype which occurs during fetal/adult development or during liver regeneration.