Partial splenic embolization (PSE) or splenectomy is widely performed to increase platelet counts for interferon (IFN) therapy. The aim of the present study was to evaluate the long-term effects of splenectomy and subsequent IFN therapy in patients with hepatitis C virus (HCV)-related liver cirrhosis (LC). The present study included 19 patients with HCV-related LC who underwent splenectomy for thrombo-cytopenia caused by hypersplenism. IFN therapy was performed in all 19 patients. The effects of splenectomy and subsequent IFN therapy on peripheral blood counts, liver function, carcinogenesis and survival rates were evaluated. Splenectomy was safely performed in all patients without major complications with the exception of portal thrombosis, which, however, it did not affect liver function when treated appropriately. Thrombocytopenia improved and IFN therapy could be performed in all the patients. A sustained virological response (SVR) was not observed in patients with genotype 1 although it was observed in 75% of patients with genotype 2. Due to severe side effects, five patients did not undergo scheduled IFN therapy. Over 5 years, the mean platelet number increased from 5.2 x 10(4) to 16.8 x 10(4)/mm3 (P<0.01) and liver function improved following splenectomy (albumin, Alb: 3.5‑3.8 g/dl; total bilirubin, T-Bil: 1.0‑0.7 mg/dl; prothrombin time, PT: 74.1‑97.7%; total cholesterol; T-cho: 140‑168 mg/dl; P<0.05). Hepatocellular carcinoma (HCC) occurred in only one patient during long‑term observation and follow‑up of the patients not presenting with HCC at entry. The results of the present study demonstrate that splenectomy followed by interferon therapy could be beneficial in patients with HCV-related LC.