The authors present the first case of a pure osteosarcoma arising in a long-standing uterine leiomyoma along with a literature review of all heterologous sarcomas arising in uterine leiomyoma. Most cases present with abnormal vaginal bleeding and symptoms related to a rapidly enlarged pelvic mass in postmenopausal women with a long-standing history of uterine leiomyoma. The histological finding of the case in this study revealed a relatively well-circumscribed tumor with a peripheral ring of leiomyoma and a central osteosarcoma. The case in this study further supported a possible pathogenesis involving the p53 gene. The prognosis may be better with low-stage tumor; however, cases with advanced stages, larger tumor size at presentation, and histological type of epithelioid angiosarcoma had poorer prognosis despite aggressive therapy.