The treatment of immune thrombocytopenia (ITP) has recently changed; however, each treatment has not only advantages, but also disadvantages, and may have unexpected complications. We describe an instructive case of ITP that was complicated by severe portal vein thrombosis during treatment with eltrombopag, an oral thrombopoietin-receptor agonist (TPO-RA) drug, plus prednisolone (PSL) concomitant splenectomy. A male ITP patient who had been receiving eltrombopag treatment for more than four years at our department underwent a splenectomy at the age of 51. Soon after splenectomy, splenic vein and portal vein thrombosis developed, while splenectomy was ineffective. The patient resumed eltrombopag treatment after thrombosis disappeared. Although fluctuations in PLT were observed, eltrombopag and PSL were used together for a while. Subsequently, lower-limb deep vein thrombosis recurred, and edoxaban tosylate was administered for a total of 8.4 months. More than three years after splenectomy, at the age of 54, abdominal computed tomography (CT) revealed a continuous thrombus extending from the intrahepatic portal vein to the superior mesenteric vein. In patients with ITP in whom splenectomy fails and treatment with a TPO-RA ± PSL needs to be continued, clinicians should be aware of the possibility of abdominal thrombotic adverse events, such as severe portal vein thrombosis, by following-up on CT imaging, not only in the short term but also in the medium-long term.