Regulation of the liver isopeptides of bovine cytochrome c oxidase is reported to be post-transcriptional. Extensive interspecies sequence homologies exist in the 3'-untranslated regions for transcripts encoding these liver isoforms, suggesting that these regions may be involved in mediating regulation of mRNA expression. To explore this possibility, several bovine tissue homogenates were assayed for any trans-acting factors that recognized the transcript encoding the liver isoform of subunit VIII (BCOL8). Such a protein factor (COLBP: cytochrome c oxidase L-form transcript-binding protein) was identified in liver, kidney, and lung tissue and was shown to require free sulfhydryl groups for activity. No binding activity, however, was found in muscle-type homogenates. Furthermore, this binding protein also recognized the subunit VIIa-liver transcript but was unable to associate with the mRNA encoding the heart isoform of subunit VIII. Intriguingly, the tissue-specific distribution of COLBP activity parallels the presence of the liver isopeptides in the mature oxidase complex. It is therefore suggested that COLBP may mediate the tissue-specific regulation of cytochrome c oxidase liver isoform mRNA expression.