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1. Effects of short-term and long-term administration of cycloheximide on rat liver mitochondrial protein synthesis have been examined and were found to be different. 2. Long-term administration of cycloheximide resulted in inhibition of total cellular protein synthesis including that of mitochondria while, at short-term intervals, 8–10% of mitochondrial protein synthesis was cycloheximide-resistant. 3. The inhibitory effect was also reflected in terms of protein synthesizing ability of mitochondria in vitro, the inhibition becoming apparent at 40 min and showing progressive increase with time. 4. The observed inhibition of mitochondrial protein synthesis by cycloheximide was not due to either inhibition of energy metabolism or alteration of amino-acid pool. 5. Cycloheximide did not enter mitochondria or sonic preparation under conditions in vitro. On the other hand, after administration of [³H]cycloheximide, significant quantities of the label were found to be associated with mitochondria and mitoribosomes. 6. These results indicated that cycloheximide reached the site of action in mitochondria under conditions in vivo but was unable to do so in vitro. 1. The results are discussed to elucidate the possible mechanisms involved in the inhibition of truly mitochondrial protein synthesis by cycloheximide. [ABSTRACT FROM AUTHOR]