Molecules coded by the major histocompatibility complex (MHC) are present on cell surfaces in most tissues, with the cells of the central nervous system and skeletal muscle as prominent exceptions. We show here that when rat skeletal muscles are rendered inactive by nerve impulse block, expression of MHC class I molecules occurs on the muscle fibres. In addition, the number of cells expressing MHC class II molecules in the muscle interstitium is increased by a factor of three after 2 weeks of impulse blockade. Similar effects obtained by denervation can be counteracted by direct electrical stimulation, Interferon‐γ‐like immunoreactivity accumulates in inactive muscle fibres, and interferon‐γ or a related cytokine could be a link between inactivity and MHC up‐regulation. These findings suggest that nerve‐evoked muscle activity influences not only the phenotype of the muscle cells themselves, but also processes in the interstitium that may increase the immunoreactivity of inactive muscle tissue.