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Background The optimal screening policy for lung cancer is unknown. Objective To identify efficient CT-screening scenarios where relatively more lung cancer deaths are averted for fewer CT screens. Design Comparative modeling study using 5 independent models. Data Sources The National Lung Screening Trial, the Prostate, Lung, Colorectal and Ovarian trial, the Surveillance, Epidemiology, and End Results program, and U.S. Smoking History Generator. Target Population U.S. cohort born in 1950. Time Horizon Cohort followed from ages 45 to 90. Perspective Societal. Intervention 576 scenarios with varying eligibility criteria (age, smoking pack-years, years quit) and screening intervals. Outcome Measures Benefits: lung cancer deaths averted or life-years gained; harms: CT-exams, false positives (including biopsy/surgery), overdiagnosed cases, radiation-related deaths. Results of Best-Case Annual screening from age 55 through 80 for ever-smokers with at least 30 pack-years and ex-smokers with less than 15 years since quitting was the most advantageous strategy. It would lead to 50% (45 to 54%) of cancers being detected at an early stage (I/II); 575 screens per lung cancer death averted; a 14% (8.2 to 23.5%) lung cancer mortality reduction; 497 lung cancer deaths averted; and 5,250 life-years gained per the 100,000-member cohort. Harms would include 67,550 false-positive tests, 910 biopsies or surgeries for benign lesions and 190 overdiagnosed cancers (3.7%; 1.4 to 8.3%). Results of Sensitivity Analysis The number of cancer deaths averted for the scenario varied across models between 177 and 862, and for overdiagnosed cancers between 72 and 426. Limitations Scenarios assumed 100% screening adherence. Data derived from trials with short duration were extrapolated to life-time follow-up. Conclusion Annual CT screening for lung cancer has a favorable benefit-harm ratio for individuals aged 55 through 80 years with 30 or more pack-year exposure to smoking.