ABSTRACT— Three types of giant mitochondria have been described in hepatocytes, and we have investigated their ultrastructural features and occurrence in alcoholic liver disease. Type I mitochondria are spherical, with a paucity of cristae. Type II are elongated and have long crystalline insertions. Type III are relatively smaller and often bizarre in shape, containing multiple crystalline insertions. We defined megamitochondria as spheroidal giant mitochondria with a diameter roughly more than one third of the hepatocyte nucleus and visible under light microscopy. Type I was the most common form of megamitochondria in livers with ALD. Megamitochondria were present in livers of 58 (27.8%) of 209 consecutive patients with alcoholic liver disease, compared with 1 (0.7%) of a series of 145 patients with non-alcoholic liver disease. The frequency and occurrence of megamitochondria varied in different types and/or stages of alcoholic liver disease. In particular, livers with alcoholic foamy degeneration had significantly increased frequency and numbers of megamitochondria compared to other patterns of alcoholic liver disease. The ultrastructural studies showed that hepatocytes containing Type I mitochondria frequently had other damaged organelles and extensive focal cytoplasmic degradation. Enzyme histochemistry showed the foamy hepatocytes containing Type I had markedly decreased staining for glucose-6-phosphatase and slightly decreased staining for succinic dehydrogenase activities, while the hepatocytes with Type II or III had normal staining. In general, Type I giant mitochondria seem more characteristic to alcoholic liver disease, or conditions that produce similar hepatic morphology. It is particularly seen in alcoholic foamy degeneration and may be part of decompensation of the hepatocytes, while Types II and III occurred in hepatocytes of both alcoholic and non-alcoholic patients and had preserved function.