Objective To investigate and analyze the constitutive characteristics and clinical significance of comorbidities in patients with stable chronic obstructive pulmonary disease (COPD) in secondary and tertiary first-class hospitals in Shanghai, China. Methods A multi-center, cross-sectional survey study was conducted on the clinical data and 33 kinds of comorbidities (8 major categories) collected from 532 stable COPD patients in the respiratory and critical care medicine departments of 14 secondary and tertiary first-class hospitals in Shanghai from Oct. 2018 to Aug. 2019. The comorbidities were scored by Charlson comorbidity index (CCI). According to the COPD assessment test (CAT) score and modified British Medical Research Council (mMRC) score, or the exacerbation times of COPD over the past year, the patients were divided into multi-symptom (CAT score ≥ 10 or mMRC score ≥ 2) and few-symptom (CAT score<10 and mMRC score 0-1) groups, or frequent exacerbation (FE, times of exacerbation ≥ 2 over the past year or ≥ 1 but resulting in hospitalization) and non-frequent exacerbation (NFE, no exacerbation or one exacerbation but no need for hospitalization) groups. The constitutive characteristics of the comorbidities were compared among different groups. Logistic regression analysis was used to investigate the correlation between comorbidities and multiple symptoms and FE in the stable COPD patients. In addition, the patients were also divided into high-CCI (≥ 4) and low-CCI (<4) groups, and the clinical characteristics were compared between the two groups. Results The average age of 532 patients was (70.44±8.98) years, with 472 (88.7%) males; the smoking index was 30 (20, 42) pack-years; and the proportion of the patients with comorbidities was 73.9% (n=393). The top four comorbidities in order were pulmonary hypertension (n=182, 34.2%), hypertension (n=144, 27.1%), bronchial asthma (n=135, 25.4%) and metabolic syndrome (n=122, 22.9%). According to the systematic classification, the top four were chronic lung diseases (n=221, 41.5%), allergic diseases (n=183, 34.4%), cardiovascular diseases (n=172, 32.3%) and metabolic diseases (n=141, 26.5%). The proportions of patients with comorbidities were 72.4% (317/438) and 80.9% (76/94) in the multi-symptom and few-symptom groups, respectively, with no significant difference (P>0.05). The proportions of patients with comorbidities were 71.5% (191/267) and 76.2% (202/265) in the FE and NFE groups, respectively, with no significant difference (P>0.05). Compared with the NFE group, the proportion of patients with bronchiectasis was significantly higher in the FE group (11.6%[31/267]vs 6.0%[16/265], P=0.024); multivariate logistic regression analysis showed that bronchiectasis was a risk factor of FE in COPD patients (odds ratio[OR]=2.127, 95% confidence interval[CI]1.114-4.060, P=0.022). Compared with the low-CCI group, the age, smoking index, course of COPD and fractional exhaled nitric oxide (FeNO) were significantly higher in the high-CCI group (76[71, 82]years vs 66[61, 69]years, 30[20, 50]pack-years vs 30[20, 40]pack-years, 8[3, 10]years vs 7[3, 8]years, 39×10^-9[22×10^-9, 50×10^-9]vs 28×10^-9[19×10^-9, 45×10^-9]), and the forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC) before inhaling bronchodilator were significantly lower ([1.02±0.39]L vs[1.21±0.52] L,[1.97±0.60]L vs[2.33±0.77]L) (all P<0.05). Conclusion The incidence of comorbidities in stable COPD patients in Shanghai, China is high and is not affected by multior few-symptom or FE, and the main comorbidities are chronic lung diseases, allergic diseases, cardiovascular diseases and metabolic diseases. Patients with high-CCI are usually elder, with long course of COPD or poor lung function. Bronchiectasis may be one of the risk factors of FE in COPD patients, and early diagnosis and active intervention can improve the management and prognosis of COPD.