The role of extracellular matrix proteins on the expression of human liver-specific genes has been investigated. Cytochrome P450 2D6 and albumin are two liver-specific genes which are constitutively expressed in hepatocytes. Primary human hepatocytes were cultured on different extracellular matrix proteins, namely collagen, fibronectin, a combination of collagen/fibronectin and EHS-laminin rich gel, and under different culture conditions. After 48 h in culture, primary human hepatocytes showed a peak in DNA-synthesis associated with a downregulation of liver-specific expression of albumin and P450 2D6, indicating the dedifferentiation of the hepatocytes. Differentiation and expression of liver-specific genes started to increase subsequently. Redifferentiation as determined by albumin and P450 2D6 levels was more pronounced if hepatocytes were seeded on fibronectin, compared to cells seeded on EHS-laminin rich gel, collagen or a combination of collagen and fibronectin.