The Fas receptor (APO-1/CD95) is expressed on hepatocytes and is thought to be important in triggering apoptosis after ligation by the Fas ligand carried on cytotoxic T cells. Recent evidence has shown that several splice variants of Fas exist, the major one of which (FasTMDel) may produce a soluble protein which can modulate apoptosis by interacting with ligand. There are no data on the expression of splice variants of Fas in liver disease. RNA was extracted from needle biopsies from 13 patients with hepatitis C virus (HCV) infection and six normal liver samples. By reverse transcriptase polymerase chain reaction (RT-PCR) FasTMDel expression was demonstrated at the mRNA level, in both normal and HCV-infected liver. Quantitative PCR demonstrated an increase in Fas transcript relative to FasTMDel in HCV infection. This difference is due to an induction of Fas, with FasTMDel remaining at constant levels in the two groups. If translated into protein, liver cells may express more Fas and thus be susceptible to apoptosis inducible by ligand-bearing cytotoxic T cells. These findings suggest that mechanisms exist to regulate the differential splicing of Fas and FasTMDel dependent on the cell's environment. The degree of alteration in the levels of Fas relative to FasTMDel occurred independently of the ALT levels and histological grading of the HCV-infected cases. However, an association was noted between increasing Fas:FasTMDel ratio and log viral load in the liver, measured by competitive PCR.