Studies indicate that proteins of hepatitis C virus (HCV) disturb expression of cell-cycle-related proteins. A disturbed cell-cycle control is a hepatocellular carcinoma (HCC) risk factor in patients with HCV-related liver damage. The present study aimed to analyse the cellular expression of p21/Wafl/Cipl (p21) in long-lasting chronic hepatitis C (CH-C), its correlation with the key oncogenic HCV proteins (C, NS3, NS5A), other cell-cycle-related proteins (PCNA, Ki-67, cyclin D1, p53) and selected clinical data. Archival liver biopsies, obtained from patients with CH-C, normal livers, and hepatocellular carcinoma (HCC) specimens were analysed by immunocytochemistry and ImmunoMax technique. In CH-C overexpression of p21 protein was demonstrated. Positive correlations of p21 protein expression in CH-C involved age of the patients, grading, and liver steatosis. Moreover, expression of p21 correlated significantly with expression of p53 protein, of D1 cyclin and Ki-67. Although Ki-67 antigen was related to p21 expression, only Ki-67 expression proved to be directly related to liver staging. Expression of the NS3 protein, which prevailed in CH-C patients, manifested correlation with p21 expression, and that of cyclin D1. In presence of preserved potential for regeneration, overexpression of p21 indicates inhibition of cell cycle in hepatocytes, which probably plays a protective role for the chronically damaged cells. Out of the three HCV proteins only NS3 seems to affect control of p21 protein expression in in vivo infection. Nevertheless, the studies indicate that neither expression of p21 protein nor that of viral NS3 protein can serve as a marker of progression of CH-C to HCC in vivo.