OBJECTIVES: To evaluate lifetime clinical effectiveness and cost-effectiveness of different antiviral treatment (AVT) strategies in patients with chronic hepatitis C (CHC) using recent German guidelines, that recommend basing drug dosage, intended treatment duration and early stopping rules on the genotype of the hepatitis C virus (HCV). METHODS: The German Hepatitis C Model (GEHMO), a validated Markov model, was used to project clinical events, life expectancy, QALYs, and lifetime costs for the following AVT strategies: 1) no AVT (NoAVT); 2) Interferon alfa-2b plus ribavirin for 48 weeks (IFN); 3) Peginterferon alfa-2b plus ribavirin for 48 weeks (PEG); and 4) Peginterferon alfa-2b plus ribavirin according to the German guidelines with genotype-dependent AVT duration, dosing and early stoppage in HCV-positive patients after 12 weeks (GUIDE). Incremental cost-effectiveness ratios (ICER) were calculated from a societal perspective. Clinical and drug utilization data were derived from a clinical trial and from a survey of German hepatologists. RESULTS: Combination therapy with peginterferon alfa-2b and ribavirin (PEG or GUIDE) reduced the 20-year risk for decompensated cirrhosis, hepatocellular carcinoma, liver transplantation, and liver-related death by more than 50%, compared to no antiviral treatment. PEG increased life expectancy by 5.0 life years and GUIDE increased life expectancy by 4.9 years compared to NoAVT. GUIDE dominated IFN, so compared to NoAVT, discounted ICERs were 1500€/QALY for GUIDE and 3300€/QALY for PEG. GUIDE saved 3950€ per patient. Moving from GUIDE to PEG was associated with an ICER >100,000 EUR/QALY. CONCLUSIONS: Administering combination therapy with peginterferon alfa-2b and ribavirin in accordance with the new German guidelines should allow tailoring treatment efficiently to HCV genotype, body weight, and early viral response in patients with minimal loss of effectiveness. Antiviral treatment according to the new German guidelines and should be cost-effective compared to other well-accepted medical interventions.