Background: COPD increases the risk for lung cancer, but two-thirds of LC cases occur in individuals without COPD. Further, more than half of lung cancers (LC) occur in individuals who do not meet age and/or smoking history eligibility criteria low-dose CT (LDCT) lung cancer screening. Thus, there is a need to develop biomarkers that improve on current demographic criteria to determine eligibility for screening. We previously identified a biomarker for the early detection of lung cancer by quantifying the prevalence of TP53 mutations present in the large airways. In this study we evaluated performance of this LC biomarker in subjects with or without COPD. Methods: Subjects undergoing standard of care bronchoscopy were recruited into an IRB-approved research study wherein soft brush biopsies of airway epithelial cells (AEC) from the large airways were collected. DNA extracted from bronchial brush specimens was sequenced by PCR-amplicon library NGS. Using synthetic internal standards to control for sequencing error, variant allele fraction (VAF) was observable down to 0.01%. The TP53 biomarker was measured in AEC DNA from 38 non-COPD subjects, including 16 with cancer and 22 without cancer, and 21 COPD subjects, 14 with cancer, and 7 without cancer. Results: The TP53 biomarker differentiated between cancer and non-cancer subjects in the absence of COPD with a receiver operator characteristics (ROC) area under the curve (AUC) value of 0.84. The TP53 biomarker also differentiated between cancer and non-cancer in patients diagnosed with COPD with an AUC of 0.78 in ROC analysis. Conclusions: The TP53 biomarker performed well differentiating between cancer and non-cancer status in both COPD and non-COPD subjects. Application of the TP53 mutation prevalence biomarker is expected to have particular value when applied to identify non-COPD subjects at risk for lung cancer. Subjects without COPD who develop lung cancer typically were ineligible for LDCT screening due to correspondingly lower smoking history and age. We plan to validate these associations in larger case-control studies. If validated, this biomarker, alone or in combination with demographic criteria, may enable identification of a large number of subjects at high risk for lung cancer who currently do not qualify for LDCT screening based on demographic criteria alone.