Alpha-1-antitrypsin deficiency has long been known to cause liver cirrhosis in man, but whether it does so in the dog is uncertain. To investigate this point 57 dogs with clinically and histopathologically diagnosed chronic liver disease were examined. Isoelectric focusing of blood serum from these dogs and from 25 clinically healthy dogs revealed three different types of alpha-1 antitrypsin, designated F(fast), I(intermediate) and S(slow). They appeared in both homozygous and heterozygous forms, the F type being seen most frequently. The I type was more common in cocker spaniels than in other breeds. Immunostaining for alpha-1 antitrypsin revealed that 37 diseased dogs had alpha-1 antitrypsin in the cytoplasm of their hepatocytes. Of these, 21 dogs had globular alpha-1 antitrypsin inclusions in the endoplasmic reticulum, indicating aggregated protein. Accumulated alpha-1 antitrypsin was found most frequently in dogs having the I and S types of alpha-1 antitrypsin, either homozygously or heterozygously. With a few exceptions, F-homozygotic dogs had no hepatocellular alpha-1 antitrypsin accumulation. As alpha-1 antitrypsin aggregation is lethal to hepatocytes and as cell death attracts mononuclear blood cells whose cytokines induce continued alpha-1 antitrypsin synthesis with subsequent risk of further alpha-1 antitrypsin accumulation, liver disease may thus be maintained. Whether alpha-1 antitrypsin aggregates actually initiate liver disease in dogs, as in man, remains to be elucidated by further biochemical investigation of the three canine alpha-1 antitrypsin types found.