Hypoxic/ischemic encephalopathy in a cloned American Quarter horse foal was initially associated with placental insufficiency and exacerbated by protracted hypotension during anesthesia for a surgical procedure. The foal, born at the Texas A&M Veterinary Medical Center, was diagnosed at birth with neonatal maladjustment syndrome that was accompanied by dysmaturity, muscle contracture of the front limbs, and a blood clot within the lumen of the urinary bladder. Seizures that developed after anesthesia were attributed to hypoxia/ischemia during anesthesia and culminated in death. Macroscopically, the cerebrum had flattened cerebral gyri with shallow sulci, yellowish cortical discoloration, and apple-green autofluorescence (under 365-nm ultraviolet light) at the cortical/white matter junction. Microscopically, there was laminar cortical necrosis with prominent diffuse ischemic change of neuronal cell bodies. The white matter had prominent rarefaction with focal axonal and myelin degeneration and focal macrophage (gitter cell) accumulation. Additionally, there was astrocytic hypertrophy with gemistocyte formation. The chorioallantois was diffusely thickened in the area corresponding to the uterine horns. Histologically, microcotyledons were markedly attenuated with absence of chorionic villi.