Objective To observe the relationship of serum levels of homocysteine (HCY) and chemokine C-C motifligand 2 (CCL2) with cognitive impairment in COPD patients with different degrees of emphysema. Methods Sixty-twoCOPD patients identified according to emphysema phenotype classification and admitted from January 2016 to March 2017 were recruited in the study. There were 37 cases in emphysema 1-2 grade and 25 cases in emphysema 3-4 grade. Simultaneous 30 healthy subjects undergoing physical examination were recruited as control. Montreal cognitive assessment (MoCA) scale investigation and serum HCY and CCL2 test were completed. Relationship analysis was conducted on serum HCY, CCL2 levels with cognitive impairment in the COPD patients with different degrees of emphysema. Results Compared with the 1-2 grade subgroup, the PaO2 was lower, PaCO2 was higher, the plasma HCY and CCL2 levels increased in the 3-4 grade subgroup with significant differences (all P<0.05). MoCA total score and subscores were relatively low in the COPD group with emphysema than the control group (except visuospatial ability scores in the 1-2 grade subgroup). MoCA scores were statistically lower in the 3-4 grade subgroup than those in the 1-2 grade subgroup (allP<0.05). Correlation analysis showed that HCY and CLL2 levels were negatively correlated with MoCA scores and subscores (P<0.01), and HCY and CLL2 were positively correlated (bothP<0.01). The area under the receiver operating characteristic curve of HCY and CLL2 for evaluating cognitive impairment was 0.79 and 0.97, respectively. Conclusion In patients with different degrees of emphysema phenotype, serum HCY and CCL2 levels are increased in different degree, and the degree of emphysema is closely related with cognitive dysfunction.