In order to characterize the cytological features of highly differentiated hepatocellular carcinoma (HCC), a comparative morphometric study was made by observing 30 cases of HCCs and controls (normal, cirrhotic, and atrophic livers). Among trabecular HCCs, normotrabecular subtype (1-2 cell thick cell plate) usually showed minimal cytological atypism and was categorized as well or highly differentiated HCC. Using an image analyzer, the following 4 parameters were applied to quantitate the hepatocyte changes: mean cell size (C), mean nuclear size (N), nucleocytoplasmic (N/C) ratio and a coefficient of variance (CV = index of anisokaryosis). In normotrabecular HCCs, C was slightly but significantly reduced when compared with normal and cirrhotic livers (t-test: p less than 0.005). The value was further reduced in mid- and macrotrabecular HCCs. Normotrabecular HCCs showed almost the same N value as normal and cirrhotic livers but displayed significantly a higher N/C value than those of controls (t-test: p less than 0.001). The N/C ratio became even greater in other types of HCCs. While CV was relatively constant in other HCC groups and controls, it was extremely high in the pleomorphic type of HCC and liver cell dysplasia. The results indicated that a reduction in C and increase in N/C ratio, which appear as "nuclear crowding" in histological specimens, actually occurs in well differentiated HCC. For the histologic diagnosis of well differentiated HCC, it would be very important to examine liver specimens with these observations in mind.