Two uncouplers of mitochondrial oxidative phosphorylation [2,4-dinitrophenol (DNP) and carbonylcyanide-m-chlorophenylhydrazone (CCCH)] were infused intra-arterially into a branch of the lower abdominal aorta of anesthetized rats over a 60-180 min period. An acute, severe, hypermetabolic state with systemic lactic acidosis and stiffness of the lower extremeities developed. In the plantaris muscles, by histochemistry, numerous "ragged red" fibers were present after the infusion. The "ragged red" areas presumably represented an absolute increase in mitochondrial mass in affected muscle fibers. By electron microscopy, linear inclusions were present in the intracristal space of many mitochondria. Simultaneous infusion of DNP and chloramphenicol, an inhibitor of mitochondrial protein synthesis, prevented the formation of ragged red fibers but not the intracristal inclusions. Infusion of relatively large amounts of oleic acid produced histochemical and electron-microscopic changes similar to those caused by the uncouplers. A possible pathogenesis of these reversible mitochondrial changes was discussed and their potential relevance to morphologic abnormalities of skeletal muscle mitochondria in human diseases was reviewed.