BACKGROUND: COPD is associated with cardiovascular and renal dysfunction. Cystatin C (CysC) is a biomarker of renal function and an independent risk factor for all-cause and cardiovascular mortality among elderly persons. The aim of the study was to examine the prognostic role of CysC for in-hospital mortality in subjects with a COPD exacerbation. METHODS: Upon admission, serum CysC levels and arterial blood gas analysis from 477 subjects with a COPD exacerbation were measured. Clinical characteristics were also recorded. A receiver operating characteristic curve analysis was used to determine the level of CysC that discriminated survivors from nonsurvivors. Univariate and multiple logistic regression analyses were used to identify the risk factors for in-hospital mortality. To reduce the influence of confounders, subgroup analyses were performed according to the comorbidities, including states of heart failure, renal dysfunction, and pH, P aCO 2 , and P aO 2 levels. RESULTS: During the in-hospital period, 59 subjects died, and 418 subjects recovered. The decedent group showed lower pH (7.27 ؎ 0.17 vs 7.38 ؎ 0.06, P < .001), higher CysC (2.21 ؎ 1.05 mg/L vs 1.39 ؎ 0.54 mg/L, P < .001), higher P aCO 2 (77 ؎ 39 mm Hg vs 48 ؎ 14 mm Hg, P < .001), and lower P aO 2 (74 ؎ 32 mm Hg vs 84 ؎ 26 mm Hg, P < .001) levels. The area under the receiver operating characteristic curve for the CysC prediction of death was 0.77 (95% CI 0.70 -0.84). CysC values >1.59 mg/L were associated with significantly higher inhospital mortality (relative risk ؍ 5.49, 95% CI 3.24 -9.32, P < .001). Multiple logistic regression analysis showed that pH <7.20, CysC >1.59 mg/L, and heart failure were independent predictors of in-hospital mortality. The subgroup analysis showed that the comorbid states of renal dysfunction, congestive heart failure, and the levels of pH, P aCO 2 , and P aO 2 did not alter the conclusion that CysC was a mortality risk factor for subjects with a COPD exacerbation. CONCLUSION: CysC was a strong and independent risk factor for hospital mortality secondary to COPD exacerbation.