The impact of self-reported chronic obstructive pulmonary disease (COPD), coronary artery disease (CAD), stroke, and diabetes mellitus (DM) on diagnostic difficulties in lung cancer screening was investigated using data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Individuals from the lung cancer screening trial’s usual care and intervention (annual chest x-ray) groups with a 20 pack-year smoking history and who had undergone an invasive procedure were included in the analysis. To determine the impact of comorbidity on procedural complications, researchers used multivariate logistic regression analysis. The incidence of significant or moderate problems was the primary outcome. Older age (OR=1.03 per year, P=0.001), CAD history (OR=1.40, P=0.03), DM history (OR=0.41, P=0.001), current smoking status (OR = 1.46, P ≤ .001), a surgical biopsy (OR=7.39, P<0.001), needle biopsy (OR=1.94, P<0.001), and other invasive procedure (OR=1.58, P<0.001) were all associated with a high-risk complication. Investigators found no link between complication and stroke history (OR=0.84, P=0.53) or COPD history (OR=1.27, P=0.06). Patient and procedure-level factors might influence lung cancer screening. Data about individual risk factors and high-risk complications should be included in diagnostic algorithms to maximize clinical benefit while minimizing harm. The risk variables indicated here should be researched and validated further.