Background <p>Immune checkpoint inhibitors (ICIs) therapy has revolutionized anti-cancer therapy, with lung cancer exhibiting sustained clinical responses to it. However, there remains a lack of research into the risk factors of serious infections in patients with lung cancer following ICIs therapy. Therefore, we aimed to investigate the incidence and risk factors of serious infections in these patients.</p> Methods <p>Medical records were retrospectively collected and reviewed from 710 patients with lung cancer receiving ICIs therapy at Zhongshan Hospital between January 2021 and February 2023. Serious infections were defined as infections requiring hospitalization or parenteral antimicrobials occurring at any time from the initiation of the ICIs therapy to 3&#xa0;months after its discontinuation.</p> Results <p>Among the study population, 191 patients had suffered from serious infections, with an overall infection rate of 26.90% during an average follow-up period of (432.62 ± 377.09) days. The predominant site of infection was the lung (75.61%), and the most prevalent pathogens were bacteria (85.07%), followed by <i>Mycobacterium tuberculosis</i> (6.47%), viruses (4.98%), and fungi (3.48%). In addition to chronic obstructive pulmonary disease (COPD), asthma, and systemic glucocorticoids use, low lymphocyte count and CD4/CD8 ratio were identified as independent risk factors (all <i>p</i> &lt; 0.05).</p> Conclusion <p>Laboratory parameters may serve as strong predictors for serious infections in patients with lung cancer following ICIs therapy. Chronic airway diseases including COPD and asthma should be managed effectively. Systemic glucocorticoids should be used prudently to prevent serious infections in these patients.</p>