Chronic hepatitis C patients often fail to respond to interferon‐based therapies. This phase III study aimed at confirming the efficacy and safety of glycyrrhizin in interferon + ribavirin‐based therapy non‐responders. A randomised, double‐blind, placebo‐controlled, comparison of glycyrrhizin, administered intravenously 5×/or 3×/week, and 5×/week placebo for 12 weeks to 379 patients, was followed by a randomised, open comparison of glycyrrhizin i.v. 5×/versus 3×/week for 40 weeks. Primary endpoints were: (1) the proportion of patients with ≥50% ALT (alanine aminotransferase) reduction after 12 weeks double‐blind phase, and (2) the proportion of patients with improvement of necro‐inflammation after 52 weeks as compared with baseline. The proportion of patients with ALT reduction ≥50% after 12 weeks was significantly higher with 5×/week glycyrrhizin (28.7%, P < 0.0001) and 3×/week glycyrrhizin (29.0%, P < 0.0001) compared with placebo (7.0%). The proportion of patients with improvement in necro‐inflammation after 52 weeks was 44.9% with 5×/week and 46.0% with 3×/week, respectively. Glycyrrhizin exhibited a significantly higher ALT reduction compared to placebo after 12 weeks of therapy and an improvement of necro‐inflammation and fibrosis after 52‐weeks treatment. Generally, glycyrrhizin treatment was well tolerated.