Cuprizone affects the liver of treated mice in a random manner, causing no appreciable change in some cases and inducing the formation of megamitochondria with altered properties in others. Lack of a full appreciation of this variability may be at the origin of some discrepancies in published work dealing with the properties of cuprizone mouse liver mitochondria (CMLM). CMLM from fully affected livers were remarkably labile and difficult to isolate in a coupled state by homogenization and centrifugation techniques. The integral respiratory chain proteins of CMLM were functionally normal, with the exception of succinic dehydrogenase which showed considerable inhibition. Coupled morphological and functional analysis provided evidence that these properties were independent of CMLM size, a matter which had remained doubtful thus far and bears on the validity of literature reports.