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Background: Lung cancer screening trials generally enroll motivated, relatively healthy, and adherent populations. We therefore evaluated the prevalence and effects of comorbidities in a real-world population undergoing low-dose computed tomography (LDCT) scans., Patients and Methods: We calculated the Charlson Comorbidity Index (CCI) of patients for whom an initial low-dose computed tomography (LDCT) for lung cancer screening was ordered between February 2017 and February 2019 in an integrated safety-net healthcare system. We examined the association between CCI and initial LDCT completion using multivariable logistic regression, assessed the association between specific medical comorbidity and LDCT completion using Chi-square test or Fisher's exact test as appropriate, and examined the association between CCI and LDCT Lung-RADS results using Fisher's exact test., Results: A total of 1358 patients were included in the analysis. Mean age was 63 years, 57% were women, and 50% were Black. Patients had moderate comorbidity burden (median CCI 3) with chronic pulmonary disease the most common comorbidity. Overall, 943 LDCT (70%) were completed. There was no difference in 30-day, 90-day, or 1-year completion rates of initial LDCT according to CCI. However, 30-day LDCT completion rates did increase over time (P < .001). Lung-RADS scores were not associated with CCI., Conclusion: In a real-world setting, patients undergoing lung cancer screening have moderate comorbidity burden. The degree and type of medical comorbidity are not associated with initial screening completion or results. Timeliness of LDCT completion may improve as program experience increases., (Copyright © 2022. Published by Elsevier Inc.)