A total of 39 hepatitis C virus-positive cirrhotic patients with hypersplenism received partial splenic embolization (PSE). Because PSE increased platelet and white blood cell counts compered to baseline levels, all the patients were treated with interferon (IFN)-based therapy. The transient virological response (TVR) rate was 53.8% (21 of 39). In univariate analysis, the significant factors associated with TVR were as follows: age ≤ 62 years, platelet counts ≥ 8.3×10⁴/µl, alpha-fetoprotein levels ≤ 18.4 ng/dl, IL28B (rs8099917) TT genotype, and telaprevir-based therapy. The sustained virological response (SVR) rate was 37.8% (14 of 37). In univariate analysis, the significant factors associated with SVR were as follows: cholinesterase levels ≥ 180 U/l, IL28B TT genotype, platelet counts ≥ 8.3×10⁴/µl, albumin levels ≥ 3.8 g/dl, age ≤ 61 years, and indocyanine green retention rates at 15 min ≤ 30.5%. In patients who achieved TVR, IFN-based therapy increased albumin and cholinesterase levels and decreased alpha-fetoprotein levels, compared to those of baseline levels. The incidence of hepatocellular carcinoma was lower in patients who achieved TVR than in those who failed. In conclusion, if the cirrhotic patients with hypersplenism would achieve TVR by IFN-based therapy after PSE, improvement of liver functions and prevention of hepatocarcinogenesis might be expected.