Abstract: Aims/Background: The morphologic differential diagnosis of hepatocellular nodules (HCN) is frequently difficult and objective criteria would be useful in the categorization of such lesions. This study evaluated the proliferative activity of HCN, including regenerative, macroregenerative (MRN), cirrhotic, dysplastic, and hepatocellular carcinoma (HCC), as well as intranodular cytologic changes such as bile-stained hepatocytes, eosinophilia, clear, large cell (LCC) and small cell (SCC) change, by comparing the cellular density (CD), labeling indices (LI) and density (DP) of two proliferation markers. Methods: Routinely processed tissue sections from 45 HCN from 17 adult liver explants were studied by immunohistochemistry for PCNA and Ki-67 (MIB-1). Results: A progressive increase in LI from regenerative to dysplastic nodules to HCC was observed with both proliferation markers. The values of the two markers were significantly correlated (p < 0.001). CD, PCNA and MIB-1 LI and DP values were significantly lower in regenerative compared to dysplastic nodules or HCC. MRNs had lower PCNA and MIB-1 LI and DP than regenerative nodules, but similar CD. There were no statistically significant differences in CD, PCNA, and MIB-1 LI and DP between dysplastic nodules and HCC, comparing high versus low grade dysplasia, or HCC smaller than 2 cm with those larger than 2 cm. The CD and proliferation indices LI and DP were higher in HCC than in the surrounding non-neoplastic parenchyma. Lesions with clear cell, eosinophilic and large cell change had CD, PCNA and MIB-1 indices similar to those of regenerative nodules, while these were lower in bile-stained hepatocellular lesions (p < 0.01). SCC showed CD, PCNA and MIB-1LI and DP similar to HCC and higher than surrounding regenerative lesions (p < 0.003). Conclusions: Our results suggest that PCNA and MIB-1 values are closely correlated in HCN. Regenerative nodules are characterized by low cellular proliferation, while dysplastic nodules are usually highly proliferative lesions and may represent an early stage in hepatocarcinogenesis. Hepatocellular lesions characterized by bile stained hepatocytes, eosinophilic, clear and large cell change have low proliferation rates and may not be significant for the development of malignancy.