Pathologic alterations induced by corticosteroid administration were evaluated in the respiratory muscles and compared to those in the peripheral skeletal muscles of the rabbit. Alterations in gross and microscopic pathology as well as histochemistry were determined in the diaphragm, intercostal, sternocleidomastoid, extensor digitorum longus, and soleus muscles following 3 wk of intramuscular cortisone injections. Corticosteroid administration induced significant pathologic changes in all the muscles except the soleus. Although gross pathologic changes were greatest in the extensor digitorum longus, microscopic changes were greatest in the diaphragm. Reductions in total muscle fiber volume were similar in the diaphragm, sternocleidomastoid, and extensor digitorum longus muscles. The composition of muscle fiber types and the number of fibers in a muscle were not altered in any of the muscles studied following corticosteroids. There was significant atrophy of individual muscle fibers in all the muscles except the soleus. In the diaphragm, corticosteroids induced atrophy of all fiber types, including type I fibers. Atrophy of type I fibers was not present in the peripheral skeletal muscles or the other respiratory muscles. On the other hand, corticosteroids induced selective atrophy of type IIb muscle fibers in the intercostal and sternocleidomastoid muscles similar to that in the peripheral skeletal muscles. These findings suggest that the effect of corticosteroids on the diaphragm is unique, and one cannot extrapolate form the effect of corticosteroids on peripheral skeletal muscles to that in the diaphragm. In addition, these pathologic changes may have functional relevance, since atrophy of type I fibers may result in a reduction in muscle endurance.