Background: The Clinical COPD Questionnaire (CCQ) has been suggested by the Global Initiative of Chronic Obstructive Lung Disease (GOLD) as a comprehensive symptom measurement tool, which helps to classify patients in order to direct pharmacological treatment. Therefore, it is essential to understand its determinants. Objectives: To identify the determinants of the overall CCQ score and scores of its 3 subdomains among chronic obstructive pulmonary disease (COPD) patients from China. Methods: A total of 1,241 COPD patients in the outpatient department of the Second Xiangya Hospital in China were recruited. Basic information and clinical data were collected. Differences in the GOLD categories based on Modified Medical Research Council Dyspnea Scale (mMRC), COPD Assessment Test (CAT), and CCQ were compared. Multiple linear regression analyses were performed to evaluate determinant factors of the total CCQ and subdomain scores. Results: The total CCQ and/or separate domain scores significantly differed with sex, age, BMI, smoking status, biomass fuel exposure, exacerbation frequency, mMRC, CAT, and GOLD grades and groups. Subjects with asthma-COPD overlap (ACO) had worse health status based on CCQ than those with COPD alone. As for the 16 subgroups based on GOLD 2017, statistical differences in the total CCQ and functional domain scores were found among subgroups 1A–4A, 1B–4B, and 1D–4D. The mMRC classified much more patients into more symptom groups than CAT and CCQ. No significant difference was observed in the GOLD categories between the CAT and CCQ (cut point = 1.5). Multiple linear regression analysis showed that smoking status, underweight, ACO, post-bronchodilator FEV1% predicted <50%, exacerbation history, and mMRC were independently associated with the total CCQ score. Only 3 variables were significantly associated with the symptom domain: ACO, exacerbations, and mMRC; for the functional domain, age ≥75 years, ACO, post-bronchodilator FEV1% predicted <50%, exacerbation history, and mMRC were significant; female sex, underweight, frequent exacerbations (≥2), and mMRC were significantly associated with higher scores in the mental domain. Conclusions: The classification of COPD produced by mMRC, CAT, and CCQ was not identical. Smoking status, underweight, ACO, post-bronchodilator FEV1% predicted <50%, exacerbation history, and mMRC were associated with lower health-related quality of life assessed by the total CCQ score, while different subdomains of CCQ had different determinant factors.