An attempt was made to compare various morphometric parameters, including total hepatocyte number, with the in vivo clearances of aminopyrine and antipyrine in 26 cirrhotic and 14 noncirrhotic patients to evaluate the intact hepatocyte theory. Morphometric analysis was performed with a newly developed method using a computer-aided color image analyzer. Aminopyrine clearance was significantly correlated with liver volume (r = 0.434; P less than 0.05), parenchymal cell volume (r = 0.574; P less than 0.001), and most strongly with total hepatocyte number (r = 0.614; P less than 0.001) in all patients. Significant correlations were also observed between these three parameters and antipyrine clearance (r = 0.367, P less than 0.05; r = 0.663, P less than 0.001; and r = 0.807, P less than 0.001, respectively). The mean aminopyrine clearance per individual hepatocyte showed no significant difference between cirrhotic and noncirrhotic patients (3.52 +/- 1.60 x 10(-10) mL/min vs. 3.65 +/- 1.50 x 10(-10) mL/min, respectively; P greater than 0.10). Similar results were obtained for antipyrine clearance per hepatocyte (7.35 +/- 2.27 x 10(-11) mL/min for cirrhotics vs. 6.16 +/- 1.07 x 10(-11) mL/min for noncirrhotics; P greater than 0.10). Thus, the intrinsic clearances of drugs per individual hepatocyte, as originally proposed in the intact cell hypothesis, were directly evaluated for the first time, lending strong support to the intact hepatocyte theory.