Abstract: Background/Aims: We aimed to evaluate the efficacy, advantage, and safety of a 24-week regimen with high-dose interferon-α (INF-α; 6 million units thrice weekly) plus ribavirin (1000–1200 mg/day) combination therapy for 46 Taiwanese chronic hepatitis C (CHC) patients with persistently normal or near-normal alanine aminotransferase (PNALT) levels. Methods: Ninety-two age- and sex-matched CHC patients with elevated ALT levels (>2 times the upper limit of normal range) with a ratio of 1:2, treated with the same regimen, served as a control. Results: The sustained virologic response (SVR) rate was comparable between PNALT (67.4%) and elevated ALT (65.2%) groups (intention-to-treat analysis). The two groups had similar rates of discontinuation and incidence of adverse effects. Viral genotype 1b, baseline viral loads, body mass index, and age were significant factors negatively associated with SVR. Further decline of ALT levels throughout the follow-up period was observed in sustained responders of the PNALT group. None of the eight patients with ALT flares developed icteric hepatitis. The virologic efficacy was sustained in a 3-year extended follow-up period. Conclusion: high-dose INF-α with ribavirin combination therapy is effective, safe, and well tolerated in CHC patients with PNALT levels. The ALT assay might not be used as a single biochemical marker for determination of treatment consideration.