Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide, with a recently increased incidence in Egypt. Its prognosis is still poor although many advances in its clinical study. In this work the cell cycle regulation in relation to cell proliferation, as an important determinant of tumor behavior, was evaluated in HCC, as a new aspect of interest in cancer research. The present work involved 27 patients with hepatic focal lesions either being; HCC (group I; n=20 cases) or cirrhotic nodules (group II; n =7 cases). In addition, five controls (group III) with normal liver were studied. p27 production pattern, as an important and recently studied cell cycle regulator, both at mRNA and protein levels was studied by RT-PCR and immunohistochemistry (IHC) assay respectively. This in relation with IHC detection of proliferating cell nuclear antigen (PCNA) as a cell proliferation marker. The present work reported that hepatic tissue expression of p27 both at mRNA and protein levels was significantly decreased in HCC group compared to other groups. However there is no significant difference could be detected in between group II and III. Furthermore reduced p27 expression (mRNA and protein) was significantly related to tumor invasiveness, advanced clinical stage and poor cellular differentiation. While no relation could be detected between p27 expression and either of patient's age, gender, viral hepatitis status, alpha-fetoprotein, Child's grade or vascular invasion. In addition cytoplasmic expression of p27 was positively associated with increased tumor foci number and poor cellular differentiation with a stronger and higher incidence in HCC patients. The present work also reported increased positive rate of PCNA expression in HCC in comparison to other groups. PCNA in HCC, as a cell proliferation marker was found to be positively associated with increased number of tumor foci, advanced tumor invasiveness, stage and grade. PCNA expression was also increased with HBV and HCV/HBV coinfection with no other significant data in HCC. Interestingly and in contrary to our expectation, no significant relationship could be detected between the expression of p27 mRNA and p27 protein, as well as between the expression of p27 (both at mRNA and protein levels) and PCNA in HCC group, while these relations could be detected significantly in the other studied groups. In conclusion, reduced p27 and increased PCNA expressions may play a great role in hepatocarcinogenesis and suggested to be significant predictors of aggressive tumor behavior. p27 and PCNA may act independently with disturbed in between relationship in HCC that may be responsible for carcinogenesis. Whether the expression of p27 protein is regulated at the transcriptional level or by other mechanisms needs to be verified. Finally altered subcellular localization and cytoplasmic sequestration of p27 may be an alternative way to inactivate p27 with a possible evident role in HCC. These finding may help in planning new treatment strategies for HCC, however, large scale in vitro and in vivo studies are needed.