Objective To analyze the related factors of multiple bacterial infections in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Methods A total of 1622 AECOPD patients admitted in our Department of Respiratory Medicine from June 2014 to December 2018 were enrolled and retrospectively analyzed. According to the results of culture of deep sputum specimens, they were divided into non-multiple bacterial infection group and multiple bacterial infection group. The related factors of multiple bacterial infections were analyzed. SPSS statistics 20.0 was used to process the data. Chi-square test was employed for comparison between groups. Multivariate logistic regression was applied to analyze the independent risk factors for multiple bacterial infections in these AECOPD patients. Results The non-multiple bacterial infection group accounted for 89.89% (1458/1622), while the multiple bacterial infection group for 10.11%(164/1622) of the patients. Compared with the non-multiple bacterial infection group, the another group had larger percentage of those over 70 years old, history of smoking ≥10 years, disease course longer than 5 years, complications, frequency of glucocorticoid use ≥5 times/year, glucocorticoid use time within 3 months ≥7d, number of antibacterial drugs used within 3 months ≥3, number of combined antibiotics within 3 months ≥3, and blood glucose ≥11.1mmol/L (all P<0.05). Multivariate logistic regression model analysis showed that the combination of antibiotics within 3 months ≥3(OR=1.874, 95%CI 1.276-2.751; P=0.001), smoking history ≥10 years(OR=1.525, 95%CI 1.037-2.241; P=0.032), complications(OR=1.899,5%CI 1.276-2.827; P=0.002), glucocorticoid use time within 3 months ≥7d(OR=2.053,5%CI1.375-3.064; P<0.001) and age ≥70 years(OR=2.098,5%CI 1.445-3.045; P<0.001) were independent risk factors for multiple bacterial infections in AECOPD. Conclusion Older age, multiple basic diseases, long-term smoking, blind use of antibiotics and long-term use of glucocorticoids may be the main causes of multiple bacterial infections in AECOPD patients.