A 26-year-old female patient presented with right lower quadrant pain with a history of hereditary retinoblastoma ; she had undergone a unilateral ophthalmectomy in infancy. Computed tomography and magnetic resonance imaging revealed an 11 cm right lower quadrant mass. A primary mesenchymal tumor was suspected, and surgery was performed. Intraoperative findings revealed that the mass was located in the proximal ascending colon mesentery, and ileocecal resection was performed. The pathological diagnosis was leiomyosarcoma, and immunohistochemistry showed loss of retinoblastoma protein expression. Hereditary retinoblastoma is an autosomal dominant hereditary disease caused by a pathogenic germline variant of the RB1 gene. It is known to give rise to secondary malignancies such as osteosarcoma and soft tissue sarcoma, mainly triggered by radiation therapy. This case suggests the need for treatment of hereditary retinoblastoma, as the secondary sarcoma can occur ectopically without therapies, causing additional gene mutations in the long term.