Tehran University of Medical Sciences Case Reports in Clinical Practice 2538-2683 9 6 2025 07 01 289 296 EN Abhijeet Sharma Swami Vivekanand Subharti University, Meerut, India. Akansha Jain Moti Lal Nehru Medical college, Prayagraj, India. 2025 03 30 2025 04 06 Fat embolism syndrome (FES) is a life-threatening complication following long bone fractures, primarily affecting the pulmonary circulation. However, cerebral fat embolism (CFE) is a rare yet severe variant that can occur when fat emboli bypass the lungs through a right-to-left cardiac shunt, such as an atrial septal defect (ASD). In individuals with HIV on antiretroviral therapy (ART), persistent endothelial dysfunction and ART-induced hypercoagulability predispose them to an exaggerated thrombo-inflammatory state, amplifying the risk of paradoxical embolism. We describe a 14-year-old male with perinatally acquired HIV on ART who presented after a high-impact road traffic accident. The patient sustained comminuted fractures of the right femoral shaft, tibia, and femoral condyle. Initially neurologically intact (Glasgow Coma Scale [GCS] 15), he experienced rapid neurological deterioration (GCS dropped to 8), alongside respiratory distress and acute respiratory distress syndrome (ARDS)-like symptoms. Urgent evaluation with a 2D echocardiogram revealed an ASD with a right-to-left shunt, strongly supporting the diagnosis of paradoxical cerebral fat embolism. This case illustrates how trauma, combined with HIV-related endothelial dysfunction, ARTinduced hypercoagulability, and a congenital cardiac anomaly, can converge to precipitate severe neurological decline through paradoxical embolism. https://crcp.tums.ac.ir/index.php/crcp/article/view/1036 https://crcp.tums.ac.ir/index.php/crcp/article/download/1036/702