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Introduction: The presence of emphysema is common in patients with interstitial lung disease (ILD), which is designated as combined pulmonary fibrosis and emphysema (CPFE). This study aimed to examine the association between smoking, emphysema, and fibrosis in ILD patients. Methods: A total of 800 patients hospitalized for ILD at the affiliated hospital of Qingdao University, Shandong, Qingdao, China, from December 2012 to December 2020 were included in our retrospective cohort study. Participants were divided into CPFE and non-CPFE groups. The patients' clinical presentations and radiographic and laboratory findings were reviewed and compared. The two groups were then divided and compared based on smoking status. Kaplan-Meier survival analysis with log-rank testing and multivariable Cox proportional hazards regression analysis were used to compare all-cause mortality. Results: Emphysema was present in 188 (23.5%) ILD patients. Smoking was associated with increased odds of CPFE (adjusted odds ratio, AOR=2.13; 95% CI: 1.33–3.41, p=0.002). The CPFE patients had a comparable risk of death to non- CPFE patients (adjusted hazard ratio, AHR=0.89; 95% CI: 0.64–1.24, p=0.493). Smoking was not a risk prognostic factor in the whole group (AHR=1.34; 95% CI: 0.90–1.99, p=0.152) or the CPFE group (AHR=0.90; 95% CI: 0.43–1.86, p=0.771). However, a significant prognostic difference between smokers and non-smokers was found in the non-CPFE group (AHR=1.62; 95% CI: 1.02–2.58, p=0.042). In ILD patients, smoking pack-years were weakly correlated with total centrilobular emphysema (CLE) scores and total fibrosis scores (TFS), but not with total emphysema scores (TES); TFS were weakly correlated with TES. Conclusions: CPFE did not affect the prognosis of ILD. Smoking was a risk but not a prognostic factor for CPFE. However, smoking was associated with worse survival in non-CPFE patients. There was an intricate association among smoking, emphysema, and fibrosis in ILD patients. [ABSTRACT FROM AUTHOR]