Dystrophin deficiency causes Duchenne muscular dystrophy (DMD). Hypertrophic feline muscular dystrophy (HFMD) is a homologous animal model of DMD. Our objective was to investigate the early changes caused by dystrophin deficiency in skeletal muscle of cats of 3-4 and 6-9 months. Obvious histological lesions were already present in the younger cats, and they increased in magnitude over time. They consisted of multifocal areas of degeneration and regeneration with mononuclear infiltration, and a wide variation in myofiber diameter, as evidenced by significantly increased variability coefficients in muscle fiber size, myofiber splitting, central nuclei, and hypercontracted myofibers. Widespread multifocal mineralizations were frequently observed. Endomysial and perimysial fibrosis was not a feature observed in axial or appendicular muscles, but was present in the diaphragm of two cats at necropsy. There was a significant decrease in the number of type 2A myofibers in dystrophin-deficient cats at both ages. Sarcolemmal dystrophin was mostly absent in all dystrophin-deficient cats; however, a small percentage of fibers stained positive, accounting for a faint residual band in the immunoblot. Carrier females had a mosaic staining pattern with irregular staining in most fibers, or even absent staining in rare fibers. However, no histological lesions were seen. Taken together, these data provide significant baseline information for further studies on the early changes associated with dystrophin deficiency in cats, or use of young dystrophin-deficient cats in therapeutic trials.