OBJECTIVES: This study evaluated the cost-effectiveness of peginterferon alfa-2b (1.5 mcg/kg/wk) plus 800-1400 mg/day ribavirin (PEG2b 1.5/R) in patients with refractory chronic hepatitis C (HCV) whose previous combination therapy with pegylated or standard interferon alfa and ribavirin failed. METHODS: A Markov model was developed based on an open-label trial (EPIC) in which patients received PEG2b 1.5/R or no further drug therapy. Patients with genotypes 1/4 (G1/4) HCV with undetectable HCV RNA at week 12 were treated for 48 weeks; patients with detectable HCV RNA were discontinued at 18 weeks. G2/3 HCV patients were treated for 24 weeks. Data on the natural history of disease, drug and medical resource costs (2007 euros), and utility values were estimated from published literature. Using a Spanish perspective, the model estimated the incremental cost-effectiveness ratio (ICER) for PEG2b 1.5/R vs. no further treatment based on cost per quality-adjusted life year (QALY) gained over a patient’s lifetime. A second-order probabilistic Monte Carlo sensitivity analysis was conducted to assess the effects of parameter uncertainty (efficacy) on the study findings. RESULTS: In G1 and G4 patients, PEG2b 1.5/R led to higher costs (€19,300 vs. €10,100) and increased QALYs (10.62 vs. 10.15) compared with no drug therapy (ICER: €19,600 per QALY gained). In G2/3 patients, treatment costs were twice as high for the PEG2b 1.5/R regimen compared with no therapy (€22,200 vs. €10,100); the incremental gain in QALYs was greater than it was for the G1 and G4 groups (11.99 vs. 10.15) (ICER: €6,600 per QALY gained). The probabilistic sensitivity analysis suggests a 99% probability that the ICER for PEG2b 1.5/R among refractory patients is at or below a €30,000 per QALY gained threshold for both genotype groups. CONCLUSIONS: PEG2b 1.5/R is in the range of the widely accepted cost-effectiveness threshold for medical interventions in Spain.