BACKGROUND & AIMS: Despite the economic impacts of chronic liver failure (CLF) and the success of chronic disease management (CDM) programs in routine clinical practice, there have been no randomized controlled trials of CDM for CLF. We investigated the efficacy of CDM programs for CLF patients in a prospective, controlled trial. METHODS: Sixty consecutive patients with cirrhosis and complications from CLF were assigned randomly to groups given intervention (n = 40) or usual care (n = 20), from 2009 to 2010. The 12-month intervention comprised 4 CDM components: delivery system redesign, selfmanagement support, decision support, and clinical information systems. The primary outcome was the number of days spent in a hospital bed for liver-related reasons. Secondary outcomes were rates of other hospital use measures, rate of attendance at planned outpatient care, disease severity, quality of life, and quality of care. RESULTS: The intervention did not reduce the number of days patients spent in hospital beds for liver-related reasons, compared with usual care (17.8 vs 11.0 bed days/person/y, respectively; incidence rate ratio, 1.6; 95% confidence interval, 0.5-4.8; P = .39), or affect other measures of hospitalization. Patients given the intervention had a 30% higher rate of attendance at outpatient care (incidence rate ratio, 1.3; 95% confidence interval, 1.1-1.5; P = .004) and significant increases in quality of care, based on adherence to hepatoma screening, osteoporosis and vaccination guidelines, and referral to transplant centers (P < .05 for all). CONCLUSIONS: In a pilot study to determine the efficacy of CDM for patients with CLF, patients receiving CDM had significant increases in attendance at outpatient centers and quality of care, compared with patients who did not receive CDM. However, CDM did not appear to reduce hospital admission rates or disease severity or improve patient quality of life. Larger trials with longer follow-up periods are required to confirm these findings and assess cost effectiveness. Anzctr.org.au, number ACTRN 12609000403235.