Purpose: Central venous catheters (CVCs) are often necessary to treat acute brain-injured patients. Four cases of cerebral herniation immediately following central venous catheterization were the impetus for an investigation of clinical and radiologic parameters associated with this complication. Materials and Methods: This is a case series of 4 consecutive patients who experienced clinical cerebral herniation immediately following CVC placement in Trendelenburg or supine position. Clinical and computed tomography imaging findings were reviewed. Results: All 4 patients developed new-onset clinical signs of cerebral herniation (unilateral or fixed dilated pupil and Glasgow Coma Scale [GCS], 3) within 30 minutes of the procedure. All had radiographic signs of Sylvian fissure and/or basal cistern effacement on the preceding computed tomographic scan secondary to unilateral or bilateral mass lesions. Preprocedure GCS was 8 or more in all cases. Herniation was medically reversed in 3 of 4 patients, and 1 patient died of progressive brainstem ischemia. Conclusions: Trendelenburg and even flat position during CVC placement can increase intracranial pressure leading to cerebral herniation in patients with significant intracranial mass effect. Careful review of neuroimaging for signs of impending herniation before inserting CVCs and choosing an alternative treatment plan in these cases may avoid this potentially underreported complication.