OBJECTIVE To compare the expression of genes involved in p53, Wnt/beta-catenin, and retinoblastoma (Rb) 1 pathways between cirrhosis-associated hepatocellular carcinoma (HCC-C) and hepatocellular carcinoma arising in non-cirrhotic liver (HCC-NC). RESULTS The gene expression profile was analysed using oligo-DNA arrays, and then validated at protein level in a tissue microarray using immunohistochemistry. Compared with their background non-neoplastic liver tissue, HCC-C showed a significantly higher rate of p53, beta-catenin (protein only) and cyclin D1 expression, whereas HCC-NC showed a significantly higher rate of p21(Waf1/cip1) and p27(Kip1) expression. HCC-C had a significantly higher rate of p53 expression and a significantly lower rate of p21(waf1/cip1) expression than HCC-NC. There was no statistically significant association between the expression of genetic markers and tumour histological grade, underlying aetiology, or lymphovascular invasion. Aberrant beta-catenin expression was more commonly seen in single tumours in comparison with multiple tumours. Increased p16(INK4) and p21(waf1/cip1) expression was more commonly observed in large-sized tumours (>50 mm) than small-sized tumours. CONCLUSIONS Alteration of the p53 pathway plays a more important role in the pathogenesis of HCC-C, whereas alterations in cell cycle regulators p21(waf1/cip1) and p27(Kip1) play a more important role in the pathogenesis of HCC-NC.