PURPOSE: Although the mechanism of onset and progression of radiation-induced fibrosis (RIF) has been studied, most studies to date have focused on pulmonary fibrosis. There are few studies on murine RIF in the skeletal muscle, and the pathogenic mechanism remains unclear. This pilot study aimed to evaluate the feasibility to create a murine model of RIF in the skeletal muscle and analyze strain differences in fibrosis sensitivity. MATERIALS AND METHODS: Two mouse strains, C57BL/6 and C3H/He, were used. Their right hind limbs were irradiated at a dose of 25 Gy once a week for three fractions. Gastrocnemius muscles were collected at day 4, and weeks 2, 4, 8, 12, and 24 after the third irradiation and subjected to histopathological examination and immunoblotting. RESULTS: In C57BL/6 mice, chronic inflammation and an increased expression of transforming growth factor-β (TGF-β) and fibronectin were observed 2 weeks after irradiation. A significant increase in fibrosis was detected after 8 weeks. However, in C3H/He mice, the expression of TGF-β and fibronectin increased 8 weeks after irradiation, and fibrosis significantly increased after 12 weeks. Moreover, the degrees of inflammation and fibrosis were more remarkable in C57BL/6 mice than in C3H/He mice. CONCLUSION: The onset and degree of fibrosis may be associated with the expression of TGF-β and fibronectin, and inflammation, in a strain-specific manner. Therefore, a murine model of RIF in the skeletal muscle could be created using the indicated method, suggesting that the C57BL/6 strain is more sensitive to fibrosis in the skeletal muscle, as well as the lung, than the C3H/He strain. Radiation-induced fibrosis in the skeletal muscle could be detected in C57BL/6 and C3H/He mice, with C57BL/6 mice being more sensitive to fibrosis in the skeletal muscle than C3H/He mice.