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A 19-month-old girl with Cornelia de Lange-like dysmorphic features presented with left eye leukocoria. She was diagnosed with 13q deletion retinoblastoma grade 4 with high-risk features and bone marrow involvement. She underwent enucleation, and the first course of intravenous chemotherapy was initiated. On day 10 after the first chemotherapy dose, she developed digital gangrene of her left hand. She was diagnosed with acute artery occlusion and limb ischemia. Thrombophilia work-up revealed antiphospholipid antibodies, and paraneoplastic syndrome is another possible cause of digital gangrene. The patient’s left thumb and index finger were amputated. After 1 month of hospitalization, she was discharged. Before the second course of chemotherapy, the patient died of systemic metastatic retinoblastoma with respiratory failure due to pneumonia. Our postulation of the mechanism for digital gangrene was the combination of chemotherapy, paraneoplastic syndrome, and antiphospholipid syndrome. Digital gangrene could be a poor prognostic indicator in patients with retinoblastoma.