Higher coffee consumption has been associated inversely with the incidence of chronic liver disease in population studies. We examined the relationship of coffee consumption with liver disease progression in individuals with advanced hepatitis C-related liver disease. Baseline coffee and tea intake were assessed in 766 participants of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial who had hepatitis C-related bridging fibrosis or cirrhosis on liver biopsy and failed to achieve a sustained virological response to peginterferon plus ribavirin treatment. Participants were followed for 3.8 years for clinical outcomes and, for those without cirrhosis, a 2-point increase in Ishak fibrosis score on protocol biopsies. At baseline, higher coffee consumption was associated with less severe steatosis on biopsy, lower serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio, alpha-fetoprotein, insulin, and homeostatic model assessment (HOMA2) score, and higher albumin (P < 0.05 for all). Two hundred thirty patients had outcomes. Outcome rates declined with increasing coffee intake: 11.1/100 person-years for none, 12.1 for less than 1 cup/day, 8.2 for 1 to fewer than 3 cups/day, and 6.3 for 3 or more cups/day (P-trend = 0.0011). Relative risks (95% confidence intervals) were 1.11 (0.76-1.61) for less than 1 cup/day; 0.70 (0.48-1.02) for 1 to fewer than 3 cups/day; and 0.47 (0.27-0.85) for 3 or more cups/day (P-trend = 0.0003) versus not drinking. Risk estimates did not vary by treatment assignment or cirrhosis status at baseline. Tea intake was not associated with outcomes. CONCLUSION: In a large prospective study of participants with advanced hepatitis C-related liver disease, regular coffee consumption was associated with lower rates of disease progression.