Fat embolism syndrome refers to a constellation of symptoms secondary to the presence of fat globules in the lung parenchyma and/or peripheral blood circulation. The syndrome is most often seen in association with long bone or pelvic fractures and can cause significant morbidity and mortality. The present randomized double blind placebo-controlled trial was conducted to evaluate the efficacy of prophylactic corticosteroids in the prevention of fat embolism syndrome and arterial hypoxia in patients with long bone fractures. Ninety-one patients with long bone fractures were randomized to case and control groups; 38 and 53 individuals, respectively. The patients in the case group received a single dose of 10 mg/kg intravenous methylprednisolone succinate upon presentation to the emergency room. The control group received placebo (normal saline). The primary endpoints evaluated were the presence of fat embolism syndrome, based on the Gurd criteria. Total two patients with fat embolism syndrome were observed in the corticosteroid-treated group (5/2%) compared with five patients in the control (9.4%; P=0.4). Arterial hypoxemia was observed in one patient in the corticosteroid-treated group (2/6%) versus eight patients in the control group (17/0%; P= 0.07). Mean arterial oxygen was not significantly different between the two groups (P=0.07). It seems that single dose methylprednisolone succinate (10 mg/kg intravenously) is not effective as prophylaxis for fat embolism syndrome and arterial hypoxemia.