The serial sarcomere number of skeletal muscle changes in response to chronic length perturbation. The role of the intermediate filament desmin in regulating these changes was investigated by comparing the architectural adaptations of the tibialis anterior, extensor digitorum longus (EDL) and soleus from wild-type mice with those of homozygous desmin knockout mice after hindlimb immobilization. After 28 days, serial sarcomere number increased significantly in the lengthened wild-type tibialis anterior (by approximately 9%) and EDL (by approximately 17%). Surprisingly, muscles from desmin knockout mice also experienced significant serial remodeling, with the serial sarcomere number of the tibialis anterior increasing by approximately 10% and that of the EDL by approximately 27%. A consistent result was observed in the shortened soleus: a significant decrease in sarcomere number was observed in the muscles from both wild-type (approximately 26%) and knockout (approximately 12%) mice. Thus, although desmin is not essential for sarcomerogenesis or sarcomere subtraction in mouse hindlimb muscles, the results do suggest subtle differences in the nature of sarcomere number adaptation. We speculate that desmin may play a role in regulating the optimal arrangement of sarcomeres within the muscle or in sensing the magnitude of the immobilization effect itself.