BACKGROUND: Benefit of adding amantadine to antiviral therapy for hepatitis C is controversial. AIMS: We aimed to examine whether such policy enhances sustained viral response in treatment-naive patients. METHODS: 297 naive hepatitis C patients were randomized for treatment with amantadine 200mg or placebo, combined with weight-based ribavirin and 12-day high-dose interferon alpha-2b induction therapy, followed by PEG-interferon alpha-2b (1.5mug/kg/week up to 26 weeks and thereafter, 1.0mug/kg/week until week 52). Treatment was discontinued if hepatitis C virus (HCV) RNA was positive at week 24. RESULTS: 49% of patients were (former) drug users. Genotype 1 occurred in 45%, high viral load in 70% and severe fibrosis/cirrhosis in 32%, without differences between amantadine or placebo groups. 90 patients prematurely discontinued treatment, mainly because of grade 3 or 4 toxicity. Intention-to-treat analysis revealed sustained viral response in 47% and 51% of amantadine and placebo groups (p=0.49). Amantadine did not enhance sustained viral response in patients with genotype 1 or high viral load nor did it improve primary non-response, breakthrough or relapse rates. Genotype non-1 and lower pre-treatment gammaGT levels were independent predictors for sustained viral response. CONCLUSION: Adding amantadine to antiviral therapy of previously untreated chronic hepatitis C patients has no beneficial effects.