Sporadic inclusion-body myositis (IBM) is a progressive degenerative muscle disease of older persons. Abnormalities of gene-expression and RNA metabolism have recently been proposed to contribute to the IBM pathogenic cascade. We now demonstrate, using well characterized, epitope-specific antibodies, that the largest subunit of RNA polymerase II is abnormally accumulated in the cytoplasm of IBM muscle fibers, where it is co-localized with phosphorylated tau on IBM paired helical filaments. Since RNA polymerase II is a crucial nuclear factor involved in both transcription and mRNA processing, our results support the hypothesis that abnormality of either or both of those processes might be caused, in part, by pathological trafficking of RNA polymerase II, and that abnormal trafficking might be an important factor in the IBM pathogenic cascade.