BACKGROUND Craniopharyngioma is a rare benign intracranial neoplasm that is successfully managed with surgery or adjuvant radiotherapy. The malignant transformation of craniopharyngioma has seldom been reported. CASE DESCRIPTION A 30-year-old woman presented with a 5-month history of amenorrhea and was admitted to the hospital. She underwent surgical resection for three times and died at last. MRI revealed a new solid component of craniopharyngioma. Pathologic examination revealed malignant changes in the craniopharyngioma. In addition, We analyzed the expression of Ki-67, p53, VEGF, and MMP-9 in this malignant case after the third operation and in samples from 9 benign craniopharyngiomas. Immunohistochemical analysis showed that the Ki-67 index was higher in malignant craniopharyngiomas (50%) compared with benign craniopharyngiomas (3.0% ± 1.5%; range, 1.0%-6.0%). The p53, MMP-9, and VEGF protein levels were higher in the malignant craniopharyngioma compared with the benign craniopharyngiomas. CONCLUSIONS Patients with a high Ki-67 index and high p53, MMP-9, and VEGF protein levels and a new solid component of craniopharyngioma on MRI may benefit from aggressive treatment and close surveillance.