BACKGROUND Major or aggressively-extended hepatectomy (MAEH) may cause secondary portal hypertension (PH), and postoperative liver failure (POLF) and is often fatal. Challenges to prevent secondary PH and subsequent POLF, such as shunt creation and splenic arterial ligation, have been reported. However, these procedures have been performed simultaneously only during the initial MAEH. CASE REPORT A 58-year-old female with chronic hepatitis C developed a solitary hepatic cellular carcinoma with portal tumor thrombosis. Blood examination and imaging revealed a decreased platelet count and splenomegaly. Her liver viability was preserved, and collaterals did not develop, and her tumor thrombosis forced us to perform a right hepatectomy from an oncological standpoint. The estimated volume of her liver remnant was 51.8%. A large volume of ascites and pleural effusion were observed on post-operative day (POD) 3, and ascetic infection occurred on POD 14. Hepatic encephalopathy was observed on POD 16. According to the post-operative development of collaterals due to secondary PH, submucosal bleeding in the stomach occurred on POD 37. Though it is unclear whether delayed portal venous pressure (PVP) modulation after MAEH is effective, a therapeutic strategy for recovery from POLF may involve PVP modulation to resolve intractable PH. We performed a splenectomy on POD 41 to reduce PVP. The initial PVP value was 32 mm Hg, and splenectomy decreased PVP to 23 mm Hg. Thereafter, she had a complete recovery from POLF. CONCLUSIONS Our thought-provoking case is the first successfully-treated case of secondary PH and POLF after MAEH, achieved by delayed splenectomy for PVP modulation.