Background: Glioblastoma multiforme (GBM) is a highly aggressive malignant tumor known to be a great mimicker. Multicystic metastasis and cystic GBM are not rare but multicystic diffuse GBM was never reported before.

Case description: We describe here the clinical course, the radiological characteristics, and the management of a patient with a diffuse cystic brain lesion. Even though the comprehensive bacterial, fungal, and parasitic work-up came back negative twice, the radiological and biological findings of the case presented in this work mislead an experienced multidisciplinary team. In a somewhat unexpected way, the pathological results showed a high-grade glial tumor.

Conclusion: The case reported herein is an important reminder of the highly multimorph characteristics of GBM and the challenging differential diagnosis of cystic brain lesions.