To investigate whether the impairment of mitochondrial function in cirrhosis is due to a reduction in liver cell mass or whether mitochondrial function is altered specifically, we analyzed mitochondrial volume and surface density of mitochondrial membranes in control and cirrhotic rats by stereological means. Cirrhosis was induced by long-term exposure to phenobarbital and CC14. Hepatocellular and mitochondrial volumes were reduced to a similar extent, by 39% and 40%, respectively, in cirrhotic animals (p < 0.01). Thus the fraction of hepatocytes occupied by mitochondria did not differ between the two groups. Both total outer (31 ± 3 vs. 19 ± 6 m2; p < 0.01) and inner (87 ± 24 vs. 45 ± 12 m2; p < 0.01) mitochondrial membranes were significantly reduced. Membrane surface was normal per unit of mitochondrial volume, however, suggesting intact mitochondrial structure. Matrix and outer membrane enzyme activities expressed per compartment did not differ between control and cirrhotic animals. Inner membrane, in contrast, had an increased enzyme content per unit area both for cytochrome oxidase (10.3 ± 2.9 vs. 13.0 ± 1.6; p < 0.05) and ATPase (13.7 ± 1.4 vs. 21.2 ± 2.9; p < 0.01). Basal oxygen consumption measured in the perfused liver in situ was significantly reduced in cirrhotic livers (1.6 ± 0.1 vs. 1.1 ± 0.4 μmol/min−1/gm−1) but was unchanged when expressed per square meter of inner membrane. Our results demonstrate that impaired mitochondrial function is mainly due to loss of hepatocellular mass. Increased enzyme activity per unit surface area of inner mitochondrial membrane may be important to maintain mitochondrial function of the cirrhotic liver. (HEPATOLOGY 1990;12:526–532).