Abstract: Objective To investigate the value of serum endoplasmic reticulum stress (ERS) markers in evaluating frequent acute exacerbations in stable chronic obstructive pulmonary disease (COPD) patients.Methods A case-control study was conducted on 88 stable COPD patients who received treatment and were followed up for one year after discharge from Beijing Daxing District Hospital of Integrated Traditional Chinese and Western Medicine from April 2020 to December 2021. The patients’ clinical data were collected. Based on exacerbation frequency, they were divided into two groups:non-frequent acute exacerbation and frequent acute exacerbation. Both groups were compared for their clinical data and serum levels of glucose-regulated protein 78 (GRP78), CCAAT/enhancer-binding protein homologous protein (CHOP), and cysteine-aspartic acid protease-12 (Caspase-12). Logistic regression analysis was conduct to identify influencing factors of frequent acute exacerbations. Receiver operating characteristic (ROC) curves were plotted to assess the predictive value of serum GRP78, CHOP, and Caspase-12 for acute exacerbations.Results The frequent acute exacerbation group showed decreases in forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) and FEV1 percentage of predicted value, and increases in the levels of serum GRP78, CHOP, and Caspase-12, compared with the non-frequent acute exacerbation group (P<0.05). Logistic regression analysis indicated that serum GRP78, CHOP, and Caspase-12 contents were the factors influencing of frequent acute exacerbations (P<0.05). ROC curve analysis demonstrated that serum GRP78, CHOP, and Caspase-12 contents had predictive value for frequent acute exacerbations, with a combined sensitivity of 89.66% and specificity of 90.00%.Conclusions Combined detection of serum ERS markers GRP78, CHOP, and Caspase-12 has good predictive value for frequent acute exacerbations in stable COPD patients.