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Introduction Serum cystatin C (Cys-C) is an indicator of ageing, and its connection with the long-term prognosis in patients with chronic obstructive pulmonary disease (COPD) is poorly understood. We aimed to examine the association between Cys-C levels and long-term mortality in patients with COPD.Methods This cohort study used data from the China Health and Retirement Longitudinal Study (CHARLS) and the National Health and Nutrition Examination Survey (NHANES). We included patients with COPD with Cys-C data from 2011 in CHARLS and 1999–2004 in NHANES. We analysed the association between Cys-C and long-term mortality in COPD using multivariate logistic regression and Cox regression. Multiple models were adjusted to reduce potential bias. Fitted curves were used to analyse the dose-response relationship between Cys-C and long-term mortality. Receiver operating characteristic (ROC) curve and subgroup analyses were also performed.Results 1030 patients with COPD from two cohorts were included in our study. When grouped by Cys-C quartiles, the high Cys-C Q4 group was older and had higher proportions of males and a higher mortality rate. Regression analysis showed a positive association between Cys-C and long-term mortality in COPD after adjusting for covariates (CHARLS: OR=3.34, 95% CI 1.51 to 7.38, p=0.003; NHANES: HR=1.35, 95% CI 1.02 to 1.75, p=0.033). Analysing the data in a categorical fashion using quartiles, the Q4 group (CHARLS: OR=2.80, 95% CI 1.07 to 7.33, p=0.036; NHANES: HR=2.12, 95% CI 1.08 to 4.19, p=0.030) had a higher mortality rate compared with the Q1 group. The area under the curve for ROC was 73.7% (CHARLS) and 73.3% (NHANES). The results of subgroup analyses showed an interaction of sex in Cys-C and COPD mortality (p for interaction=0.035 in CHARLS and 0.042 in NHANES), with a more pronounced effect on females.Conclusions Our study found that high Cys-C was related to increased long-term mortality in patients with COPD. This association appears more pronounced in females.