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Relapse of hepatitis C virus infection after liver transplantation is universal. Standard-of-care (SOC) treatment for relapse offers less satisfactory treatment response than in nontransplanted patients. Tolerance for treatment is suboptimal and withdrawals owing to adverse events induced by treatment frequent. To improve tolerance for SOC, and ribavirin (RBV) in particular, concentration-guided RBV dosing calculated by a formula taking renal function and weight into consideration was utilized. A serum RBV concentration of 10 μm was set as the goal. All patients were given maintenance darbepoetin therapy from 2 weeks prior to initiation of treatment. In total, 21 patients with a mean age of 52 (range 25–64) years were included. The mean RBV concentration at week 4 was 10.2 and 7.36 μm in genotype 1/4 and non-1/4 patients, respectively, and 11.7 and 9.42 at week 12. The mean haemoglobin drop was 25 g/L vs 21 g/L in the genotype 1/4 and non-1/4 group, respectively, a nonsignificant difference. With this treatment approach, 80–90% of patients could be kept adherent to treatment. Sustained viral response was achieved 8/16 (50%) with low-grade fibrosis (fibrosis stage ≤ 2) vs in none of five patients with advanced fibrosis (Fibrosis stage 3 and 4), P < 0.05. We conclude that a treatment algorithm utilizing concentration-guided RBV dosing during darbepoetin maintenance therapy substantially improves tolerance and allows high adherence to a SOC treatment schedule, and that therapy needs to be initiated before advanced fibrosis is developed.