Cranioplasty is a common procedure in neurosurgical practice. However, some complications may occur after the operation. We here presented a case of bilateral skull defect and underwent cranioplasty with polyetheretherketone (PEEK) prosthesis. The patient developed epidural effusion on both sides 7 days after surgery. The effusion was light yellow and transparent, and laboratory examinations revealed normal glucose level, negative bacteriological results, and increased IgG protein concentration. The effusion disappeared after treatment with dexamethasone and drainage. We speculated that the epidural effusion was because of delayed type allergic reactions after PEEK cranioplasty. However, further studies are needed to investigate its related mechanisms.