Purpose: The aim of this study was to explore the predictive value of the chronic obstructive pulmonary disease (COPD) specific comorbidity test index (COTE) and pulmonary comorbidities for moderate-to-severe acute exacerbation and hospitalization in COPD patients. Patients and Methods: This was a retrospective cohort study. We included 470 patients with stable COPD. Patients were divided into high or low-risk comorbidity group according to whether COTE score >= 4, and pulmonary comorbidities and extrapulmonary comorbidities group according to comorbidity origin. Moderate-to-severe acute exacerbation events and other clinical parameters were compared between groups. Multifactorial analysis and Lasso regression were used to screen risk factors and establish predictive models for moderate-to-severe acute exacerbation and hospitalization. The receiver operating characteristic (ROC) curve was used to assess the value COTE score and pulmonary comorbidities in predicting moderate-to-severe acute exacerbation and hospitalization. Results: When compared with the low-risk comorbidity and extrapulmonary comorbidities group, the rate of patients with >= 2 moderate-to-severe acute exacerbations and requiring hospitalization due to acute exacerbations is higher in high-risk comorbidity and pulmonary comorbidities group (chi(2)=18.45, chi(2)=40.15, chi(2)=8.82, chi(2)=23.68). Multifactorial analysis showed that comorbid with asthma, lung cancer were risk factors for moderate-to-severe acute exacerbations, while asthma, bronchiectasis, lung cancer, and high COTE score were risk factors for patients requiring hospitalization due to acute exacerbations. The AUC for COTE > 5.5 and a combination of at least one pulmonary comorbidity as potential indication of moderate-to-severe acute exacerbations of COPD and hospitalization due to acute exacerbations was 0.667 (95% CI: 0.615, 0.719) and 0.740 (95% CI: 0.688, 0.792), respectively. The prediction models including COTE and pulmonary comorbidities can predict moderate-to-severe acute exacerbations (internal validation of AUC: 0.984, 95CI%: 0.964- 1) and hospitalization (internal validation of AUC: 0.978, 95CI%: 0.959- 0.998) of COPD. Conclusion: COTE score and a combination of at least one pulmonary disease can predict the risk of moderate-to-severe acute exacerbations and hospitalization due to acute exacerbations in patients with COPD.