Abstract: Hepatitis C virus (HCV) infection is now known worldwide to be a major risk factor for the development of hepatocellular carcinoma (HCC). The precise mechanism by which HCV causes HCC is not yet known. Mutated p53 acts as a dominant oncogene and alterations in the p53 gene are the most common genetic changes in patients with HCC. This study was undertaken to clarify the spectrum, i.e. incidence, type, and site, of p53 mutations in 25 Egyptian patients with HCV-positive HCC using immunohistochemistry (IHC), single-strand conformation polymorphism (SSCP) analysis and direct sequencing. Thirteen HCC cases showed mutation in p53 by IHC, 16 showed mutation by SSCP, however, by direct sequencing, ten patients showed p53 mutation. The 10 cases showed 13 mutations, where 3 cases showed two mutations, 2 of them were at exon 8 and one in exon 5.The highest mutation rate was scored at exon 6 and 7 (30% each) followed by exons 5 and 8 (20% each). There was no specific pattern for the types of base pair mutations. They were 2 transitions, 6 transversions, 3 deletions, and 2 insersions. Two cases showed mutations at the CpG island. The two mutations in exon number 7 were at codon 249 specific for aflatoxin contamination (AGGa AGT, Arga Ser) and codon 248 specific for contamination with vinyl chloride (CGGa TGG, Arga Trp). Another case showed a frameshift mutation (1bp insertion) in codon 177 of exon 5. The other cases showed p53 mutations that are reported for the first time. NS3 detected by monoclonal antibody in HCC sections showed positive signals in 19/25(76%) of cases. HCV-induced HCC may be a result of enhanced hepatocyte turn over in order to replace immunologically killed infected cells which in turn increases the rate of mutational events in genes such as p53.