BACKGROUND Spontaneous acute subdural hematomas (SDHs) are rare. Risk factors for development of these hematomas include conditions such as hypertension, vascular abnormalities such as aneurysm or arteriovenous malformation, or consumption of anticoagulants. METHODS Here, the authors report two patients who suffered from spontaneous acute SDH while taking fondaparinux for venous thromboembolism prophylaxis. One patient suffered from a remote episode of traumatic brain injury and underwent a decompressive craniectomy 3 weeks prior to presentation, whereas the other patient had been self-medicating with aspirin. CONCLUSIONS To our knowledge, these two patients illustrate the first cases of spontaneous acute SDH formation most likely attributed to consumption of fondaparinux.