Objective To explore the influencing factors of chronic obstructive pulmonary disease (COPD) with pulmonary infection (PI) and the changes of serum interleukin-16 (IL-16), CD40 and high mobility group protein B1 (HMGB1). Methods The clinical data of 113 patients with COPD who received treatment in our hospital from July 2020 to June 2023 were retrospectively analyzed, and the patients were divided into infected group (34 cases) and non-infected group (79 cases) according to whether PI occurred. General data of patients were collected, and serum levels of IL-16, CD40 and HMGB1 were compared between the two groups of patients, and the risk factors of PI in patients with COPD were analyzed by univariate analysis and logistics regression analysis. Results The incidence rate of PI in patients with COPD was 30.09% (34/113). The levels of IL-16, CD40 and HMGB1 in infected group were higher than those in non-infected group (all P＜0.05). Logistics regression analysis showed that smoking history, diabetes mellitus history, hospital stay≥15 d, long-term use of antibiotics and mechanical ventilation,IL-16, CD40 and HMGB1 were independent risk factors of PI occurrence in COPD (all P＜0.05). Conclusion Smoking history, diabetes mellitus history, hospital stay≥15 d, long-term use of antibiotics and mechanical ventilation, IL-16, CD40 and HMGB1 are independent risk factors of PI occurrence in patients with COPD