© 2015 American College of Physicians. Background: Lung cancer screening with low-dose computed tomography (LDCT) has been recommended, based primarily on the results of the NLST (National Lung Screening Trial). The American College of Radiology recently released Lung-RADS, a classification system for LDCT lung cancer screening. Objective: To retrospectively apply the Lung-RADS criteria to the NLST. Design: Secondary analysis of a group from a randomized trial. Setting: 33 U.S. screening centers. Patients: Participants were randomly assigned to the LDCT group of the NLST, were aged 55 to 74 years, had at least a 30-pack-year history of smoking, and were current smokers or had quit within the past 15 years. Intervention: 3 annual LDCT lung cancer screenings. Measurements: Lung-RADS classifications for LDCT screenings. Lung-RADS categories 1 to 2 constitute negative screening results, and categories 3 to 4 constitute positive results. Results: Of 26 722 LDCT group participants, 26 455 received a baseline screening; 48 671 screenings were done after baseline. At baseline, the false-positive result rate (1 minus the specificity rate) for Lung-RADS was 12.8% (95% CI, 12.4% to 13.2%) versus 26.6% (CI, 26.1% to 27.1%) for the NLST; after baseline, the falsepositive result rate was 5.3% (CI, 5.1% to 5.5%) for Lung-RADS versus 21.8% (CI, 21.4% to 22.2%) for the NLST. Baseline sensitivity was 84.9% (CI, 80.8% to 89.0%) for Lung-RADS versus 93.5% (CI, 90.7% to 96.3%) for the NLST, and sensitivity after baseline was 78.6% (CI, 74.6% to 82.6%) for Lung-RADS versus 93.8% (CI, 91.4% to 96.1%) for the NLST. Limitation: Lung-RADS criteria were applied retrospectively. Conclusion: Lung-RADS may substantially reduce the falsepositive result rate; however, sensitivity is also decreased. The effect of using Lung-RADS criteria in clinical practice must be carefully studied. Primary Funding Source: National Institutes of Health.