Hepatitis C-associated osteosclerosis (HCAO) is a very rare condition that can be observed in a small number of patients with Hepatitis C Virus (HCV) infection. HCAO is usually characterized by widespread bone sclerosis, associated with severe bone pain, and increased levels of bone turnover markers, especially alkaline phosphatase (ALP). In this report, we present the case of a 55-year-old woman who was affected by HCV and came to our attention for severe and diffuse bone pain. Radiological studies showed bone sclerosis, and bone mineral density (BMD) was markedly increased, as well as serum ALP levels. The patient was initially treated with intravenous pamidronate, which provided only a transient benefit on clinical symptoms. Then antiviral therapy for HCV (interferon-alfa and ribavirin) was started and it was effective in making the viral load undetectable. After a long follow-up period, we observed a persistent remission of bone pain, a reduction in BMD together with a progressive trend toward the normalization of bone turnover markers. In conclusion, HCAO, although rare, should be considered among the potential causes of increased bone mass in patients with HCV infection, and treatment for the underlying infection may be effective in controlling the manifestations of this disease.© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.