Background: A substantial proportion of patients with chronic hepatitis C virus (HCV) cirrhosis fail to eradicate infection and develop liver-related complications. Despite evidence that interferon-α has an antifibrotic effect, clinical trials have demonstrated that low-dose maintenance interferon does not improve outcomes in patients with compensated HCV cirrhosis following a lead-in phase of interferon. In a pilot study, we have investigated the efficacy of an escalating dose of pegylated interferon α-2a (PEG-IFN2a) as compared with standard clinical care in patients with more advanced HCV Child’s A or B cirrhosis without a lead-in phase. <p/>Methods: In a prospective study, 40 patients were randomized to receive either standard clinical care (no further antiviral therapy) or 48 weeks of treatment with PEG-IFN2a starting at 90 mcg and escalating to 180 mcg weekly if tolerated. Patients were thereafter followed for a mean duration of 41 months. The primary outcome variables were liver-related death, all-cause mortality and sustained virological response. The secondary outcomes were ‘liver-related events’ and health-related quality of life. <p/>Results: Both groups were well matched, with treatment well tolerated. The incidences of all-cause mortality (P=0.024) and nononcological liver morbidity (P=0.04) were significantly higher in the control arm after a mean of 47 months of follow-up. <p/>Conclusion: A 48-week escalating dose of PEG-IFN2a is associated with a significant reduction in all-cause mortality and nononcological liver-related morbidity in this trial. Further investigation of PEG-IFN2a is warranted for patients with advanced HCV-related cirrhosis for whom there is no other treatment and where transplantation is associated with rapid progression to cirrhosis.