Duchenne muscular dystrophy (DMD) and homologous mouse model mdx are recessive X-linked hereditary diseases and characterized by the loss of the cytoskeletal protein dystrophin. Dystrophin deficiency causes enormous dystrophic alterations such as necrotic and regenerating myofibers, centralized nuclei, infiltration of inflammatory cells and fibrosis. However, the degree of damage is very variable for mdx muscles ranging from insignificant changes in extraocular muscles to mild changes in limb muscles (EDL and soleus) and severe damage and fibrosis in the diaphragm. In contrast to the above mentioned muscles distal muscles of the foot, flexor digitorum brevis (FDB) and M. interosseus, are not well investigated histologically and not on the protein level. On the other hand many observations on Ca²⁺ influx and the function of cation channels have been made with isolated interosseus and FDB fibers without knowing whether these findings can be generalized. Therefore, following histological evaluation of normal versus mdx soleus, EDL, FDB and interosseus muscles, we have prepared the urea-soluble protein complement from these four muscles from 100 d old control and dystrophic mice. Muscle protein extracts were separated by two-dimensional gel electrophoresis and labelled with the fluorescent dye ruthenium II tris bathophenanthroline disulfonate. Then proteins with a significant change in their concentration were identified by mass spectrometry. Histological analyses showed a significantly lesser degree of central nucleation in FDB and interosseus muscles of mdx mice as compared to EDL and soleus muscle of mdx mice. Further, the well known hypertrophy of mdx muscle was only observed for the limb muscles, but not for FDB and interossei. Proteomic profiling established an altered abundance of 24, 17, 19 and 5 protein species in dystrophin-deficient soleus, EDL, FDB and interosseus muscle, respectively. Identified proteins are involved in the contraction-relaxation cycle, metabolite transport, muscle metabolism and the cellular stress response. We conclude that mdx interosseus, a muscle that is frequently used to study the mechanism of muscle fiber degeneration showed a reduced fraction of fibers with central nuclei, lack of hypertrophy and minor proteomic changes. Mdx interosseus muscle probably represents a naturally protected phenotype indicating that results solely based on the use of interosseus fibers should be regarded with caution.