The relationship between hepatocyte enlargement and intrahepatic and portal pressures was studied in a group of 163 patients with alcoholic liver disease presenting liver biopsy abnormalities, including 91 cirrhotics. For the complete group, hepatocyte surface areas were significantly correlated (r = 0.73, p < 0.0001) with pressure. Cirrhotics as a group had a mean average pressure of 20.4 ± 0.9 mm Hg, while that for noncirrhotics was 11.7 ± 0.8 mm Hg (p < 0.0001). The corresponding values for mean hepatocyte surface areas were 2,308 ± 76 μm2 and 1,692 ± 63 /μm2. In cirrhotics with corrected sinusoidal pressures (wedged hepatic vein pressure-free pressure), or intrahepatic pressures below 10 mm Hg, mean hepatocyte surface area 1,405 ± 51 μm2 was in the same area range as that of the group of noncirrhotics with similar pressures (1,410 ± 46 μm2). It is postulated that higher pressures often seen in cirrhotics are due to the existence of larger cells in these patients, rather than the existence of “regenerative” nodules. Cirrhosis per se was not a good indicator of portal hypertension and 23% of cirrhotics were shown to have pressures below 10 mm Hg. On the other hand, when hepatocyte enlargement was used as an indicator of portal pressure, it was found that pressures below 10 mm Hg occurred in only 6.8% of individuals with cell surface areas exceeding 1,700 μm2. In patients with or without cirrhosis in whom two pressure determinations were carried out simultaneously with the biopsies, it was observed that changes in pressures were followed remarkably closely by changes in cell surface areas in the same direction (91% of cases, p < 0.001). Elevated portal pressure could also be found in a group of 43 chronic alcoholics in whom 50 liver biopsies were reported as “normal.” In these, correlation between hepatocyte area and intrahepatic pressure was also highly significant (r = 0.88, p < 0.0001) with an abrupt increase in intrahepatic pressure above 10 mm Hg, for hepatocyte areas greater than 1,500 μm2. Collagen accumulation in the space of Disse has been proposed as a cause of portal hypertension. While we have confirmed that a correlation exists between Disse collagen scores and intrahepatic or corrected sinusoidal pressures, when measured at a single point in time, (r = 0.63, p < 0.0001), collagen did not follow the changes in pressure in 65% of the cases. While these observations firmly support our earlier postulation of a strong correlation between hepatocyte enlargement and the production of intrahepatic or portal hypertension, further studies should be conducted to establish causality in the association between these two factors.