To investigate the antiviral efficacy of combination therapy with pegylated-interferon alpha (peg-IFNa)-2a and ribavirin (RBV) in hepatitis C patients with liver cirrhosis after splenectomy or partial splenic embolization. Forty-nine hepatitis C patients with liver cirrhosis who were unable to use antiviral therapy because of hypersplenism were recruited for study and treated with splenectomy or partial splenic embolization. Three months later, a regimen of antiviral combination therapy was initiated with peg-IFNa-2a (once-weekly subcutaneous injection: 135 μg or 180 μg) and RBV (daily oral: 800 to 1200 mg), and was maintained for 48 weeks. The patients were followed up at treatment weeks 1, 2, 4, 6, 8, and 12. Thereafter, follow-up was conducted every four weeks. The patients were observed until 24 weeks after treatment discontinuation. Follow-up testing included liver function, blood chemistry, renal function, and HCV RNA level. Any adverse reactions were recorded. Liver cirrhosis patients complicated by hypersplenism can be treated effectively with peg-IFNa-2a/RBV combination antiviral therapy after splenectomy or partial splenic embolization. The antiviral-induced sustained viral response rates was 65.00% in cirrhotic/hypersplenic hepatitis C patients receiving splenectomy and 58.62% in those receiving partial splenic embolization. Hypersplenism patients with hepatitis C-related cirrhosis achieved a good antiviral therapeutic effect with peg-IFNa-2a/RBV combination therapy following splenectomy or partial splenic embolization. This sequence of treatment may help to decrease incidences of chronic hepatitis C-induced liver failure and liver cancer in these patients.