SARS-CoV-2 infection is linked to systemic symptoms beyond the respiratory tract, including muscle weakness, muscle pain, and fatigue (1). The underlying histopathological reasons for the involvement of skeletal muscle in coronavirus disease 2019 (COVID-19) remain incompletely understood. In the present study, we examined skeletal muscle obtained at autopsy from a subgroup of people who tested positive for SARS-CoV-2 and assessed the degree of myofiber necrosis, inflammation, and the immunohistochemical reactivity for the SARS-CoV-2 nucleocapsid protein. The main morphological finding was degeneration and necrosis of myofibers often in a focal or discontinuous manner affecting single fibers or a group of fibers, while neighboring fibers were fairly well preserved. The inflammatory infiltrates were generally scarce. The immunoreactivity for the SARS-CoV-2 nucleocapsid protein varied. There was no clear correlation between the intensity of the staining and the severity of the myofiber necrosis. Necrotic changes were found in both the groups that had been hospitalized for a long time and those that had been hospitalized for a short time or not at all, which suggests that critical illness myopathy cannot account for all the lesions observed. These results point to an atypical pattern of skeletal muscle damage in individuals who are positive for SARS-CoV-2 at the time of autopsy, a pattern that is mostly free from inflammation, and thus calls for further investigation into neurogenic, vascular, and other indirect mechanisms of muscle damage during both the acute and the post-acute phases of COVID-19.