We report the case of an 8-year-old boy with a red cell membrane disorder who developed, soon after undergoing laparoscopic cholecystectomy and splenectomy, complete thrombosis of the right branch and a partial occlusion of the left branch of the portal vein. The child was affected by a right hemiparesis because of a hypoxic-ischemic disorder that occurred in the first hours of life and was heterozygous for the methylenetetrahydrofolate reductase gene mutation 677C-T. Intravenous heparin and aspirin were initiated on postoperative day 7. Heparin treatment was switched to the subcutaneous route after the first 24 hours. The symptoms subsided 3 days after the beginning of treatment, whereas complete resolution of portal vein thrombosis was observed 2 months later. A review of the literature is reported, and the possible pathogenetic mechanisms underlying portal vein thrombosis are discussed.