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Sinusoidal obstruction syndrome (SOS) occurs in patients undergoing hematopoietic cell transplantation and chemotherapy. The chemotherapeutic drugs oxaliplatin and cyclophosphamide cause SOS. Sesame oil is a nutrient-rich antioxidant popular in alternative medicine. It contains sesamin, sesamol, and sesamolin, all of which contribute to its antioxidant property. The authors investigated the protective effect of prophylactic sesame oil against monocrotaline-induced SOS in rats.Male Sprague-Dawley rats were gavaged with a single dose of sesame oil (0.5, 1, 2, or 4 mL/kg). One hour later, those rats were gavaged with monocrotaline (90 mg/kg) to induce SOS. Control rats were treated with saline only. Aspartate transaminase, alanine transaminase, laminin, collagen, myeloperoxidase, nitrate content, lipid peroxidation, glutathione levels, matrix metalloproteinase (MMP)-9, and tissue inhibitor of matrix metalloproteinases (TIMP)-1 were assessed 48 hours after the monocrotaline gavage.All tested parameters except TIMP-1, laminin, collagen, and glutathione were higher in monocrotaline-treated rats than in saline-only-treated control rats. In sesame oil-treated rats, all tested parameters except TIMP-1, laminin, collagen, and glutathione were significantly attenuated compared with monocrotaline-only-treated rats. Sesame oil downregulated MMP-9 expression but upregulated TIMP-1 expression in monocrotaline-only-treated rats. In addition, a histological analysis of liver tissue samples showed that sesame oil showed significant protection.A single prophylactic dose of sesame oil protects against SOS by downregulating MMP-9 expression, upregulating TIMP-1 expression, and inhibiting oxidative stress.