Background Various comorbidities influence the prognosis of patients with chronic obstructive pulmonary disease (COPD). We investigated if liver fibrosis assessed using fibrosis-4 index (FIB-4) is associated with all-cause mortality in patients with COPD. Methods We included 756 patients diagnosed with COPD between 2006 and 2010. Medical records were retrospectively reviewed until 2018. FIB-4 was calculated using the following equation: [age (years) × aspartate aminotransferase (IU/L)/(platelet count (109/L) × √alanine aminotransferase (IU/L))]. Results From a total of 756 patients, 582 (76.9%) patients were categorized into survivor and 174 (23.1%) into non-survivor groups. The non-survivor group was significantly older with a higher proportion of male, smoker and lower FEV1/FVC ratio than the survivor group (all P<0.05). Various comorbidities were more frequently observed in the non-survivor group (P<0.05). In addition, the non-survivor group had significantly higher FIB-4 than the survivor group (1.8 vs 1.4, P<0.001). In multivariate analysis, older age (hazard ratio [HR]=1.05), underlying malignancy (HR=2.94), coronary artery occlusive disease (HR=1.58), higher FIB-4 (HR=1.15), and higher GOLD stage (HR=1.26) were significantly associated with the increased risk of all-cause mortality (P<0.05), whereas body mass index (HR=0.95) was independently protective for all-cause mortality (all P<0.05). The high FIB-4 (>1.57) group showed a significantly lower cumulative survival rate than the low FIB-4 (≤1.05) group (P=0.031, Log-rank test). In multivariate regression analysis, higher FIB-4 independently predicted the risk of acute exacerbation (odds ratio=1.08, P=0.034). Conclusion Higher fibrotic burden assessed using FIB-4 was independently predictive of the increased risk of all-cause mortality and acute exacerbation in patients with COPD.